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WO2020237374A1 - Dérivés d'acide picolinique et leur utilisation dans le traitement de maladies associées à un taux élevé de cholestérol - Google Patents

Dérivés d'acide picolinique et leur utilisation dans le traitement de maladies associées à un taux élevé de cholestérol Download PDF

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WO2020237374A1
WO2020237374A1 PCT/CA2020/050721 CA2020050721W WO2020237374A1 WO 2020237374 A1 WO2020237374 A1 WO 2020237374A1 CA 2020050721 W CA2020050721 W CA 2020050721W WO 2020237374 A1 WO2020237374 A1 WO 2020237374A1
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subject
compound
disease
inhibitor
compounds
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Steve Poirier
Brent Richard Stranix
Gaétan MAYER
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Institut de Cardiologie de Montreal
Montreal Heart Inst
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Institut de Cardiologie de Montreal
Montreal Heart Inst
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention is directed to picolinic acid derived compounds of Formula I, pharmaceutically acceptable salts or solvates thereof, pharmaceutical compositions including one or more compounds of Formula I, methods of
  • Plasma apolipoprotein B (ApoB) lipoproteins such as low density lipoprotein (LDL) particles, which carry the majority of total circulating cholesterol, are cleared by binding to hepatic LDL receptor (LDLR), endocytosed and catabolized.
  • LDL low density lipoprotein
  • LDLR hepatic LDL receptor
  • An induction of LDLR leading to higher absorption of LDL, very low density lipoprotein (VLDL) and chylomicron remnants has been shown to be a method for significant reduction of circulating cholesterol.
  • CVD cardiovascular disease
  • the present invention relates to a series of low density lipoprotein receptor (LDLR) inducers derived from picolinic acid esters and picolinamides, and pharmaceutically acceptable derivatives thereof (e.g., salts and solvates).
  • LDLR low density lipoprotein receptor
  • Synthesis of novel compound libraries yielded potent inducers of LDLR expression in hepatic cells and led to significant lowering of circulating cholesterol in animal model.
  • the compounds featured herein are useful for modulating LDLR activity and, in particular for inducing LDLR production and for treating elevated cholesterol and related conditions.
  • a first aspect features a compound having the structure of formula (I):
  • Y is OR 3 ;
  • Z is H, optionally substituted Ci- 6 alkyl, or -ChhOR ⁇
  • L is optionally substituted Ci- 6 alkyl or optionally substituted Ci- 6 heteroalkyl
  • Ri is H, -OH, optionally substituted Ci- 6 alkyl, optionally substituted C 5-10 heterocycle, optionally substituted Ce-io aryl, or optionally substituted C 5-10 heteroaryl;
  • R 2 is NR 5 Re or OR5;
  • each of R 3 and R 4 is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 fluoroalkyl, benzyl, phenyl, or optionally substituted C 5-10 heterocycle; or R 3 and R 4 combine to form an optionally substituted heterocycle, R 5 IS H, optionally substituted C 1 -6 alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C 1-6 fluoroalkyl, optionally substituted C 1-6 alkyl Ce-io aryl, or optionally substituted C 5-10 heterocycle;
  • R 6 is H or optionally substituted C 1 -6 alkyl
  • R 5 is methyl, propyl, cyclopropyl
  • R6 is methyl
  • X is A 3 ⁇ 4 ⁇ 5 .
  • R 5 is -CF 3 .
  • X is cyano
  • Y is OH.
  • Z is methyl or - CH 2 OH.
  • Y is OR 3 .
  • Z is -CH 2 OR 4 .
  • R 3 and R 4 combine to form an optionally substituted heterocycle.
  • the optionally substituted heterocycle is
  • Some embodiments of the first aspect features a compound having the structure of any one of compounds 1 -44 of Table 1 , or a pharmaceutically acceptable salt or solvate thereof.
  • compositions and pharmaceutically acceptable formulations containing a therapeutically effective amount of at least one compound of the present invention (e.g., at least one compound of Formula I, such as at least one of compounds 1 -44 of Table 1 ), or a pharmaceutically acceptable salt or solvate thereof.
  • the pharmaceutical composition may further include a pharmaceutically acceptable carrier, excipient, or adjuvant.
  • a therapeutically effective amount e.g., a cholesterol lowering amount
  • LDLR expression e.g., mRNA expression and/or protein expression
  • LDLR activity in a subject in need thereof (e.g., in a cell, such as a hepatic cell in a subject in need thereof) by administering to the subject a therapeutically effective amount of at least one compound of the present invention (e.g., at least one compound of Formula I, such as at least one of compounds 1-44 of Table 1 ), or a pharmaceutically acceptable salt, solvate or composition thereof.
  • the subject has been diagnosed with or is predisposed to (e.g., at a risk of developing) a disease or condition that is caused or mediated by elevated cholesterol level (e.g., an elevated cholesterol associated disease, such as atherosclerosis, hypercholesterolemia (e.g., heterozygous familial hypercholesterolemia or homozygous familial hypercholesterolemia),
  • elevated cholesterol level e.g., an elevated cholesterol associated disease, such as atherosclerosis, hypercholesterolemia (e.g., heterozygous familial hypercholesterolemia or homozygous familial hypercholesterolemia)
  • hypertriglyceridemia diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure).
  • a disease or condition that is caused or mediated by elevated cholesterol level e.g., an elevated cholesterol associated disease
  • administering to the subject a therapeutically effective amount of at least one compound of the present invention (e.g., at least one compound of Formula I, such as at least one of compounds 1-44 of Table 1 ), or a pharmaceutically acceptable salt, solvate or composition thereof.
  • the subject has been diagnosed with a disease or condition that is caused or mediated by elevated cholesterol level (e.g., an elevated cholesterol associated disease).
  • the subject is predisposed to (e.g., at a risk of developing) a disease or condition that is caused or mediated by elevated cholesterol level (e.g., an elevated cholesterol associated disease).
  • elevated cholesterol level e.g., an elevated cholesterol associated disease
  • diseases or conditions that are caused or mediated by elevated cholesterol level include atherosclerosis, hypercholesterolemia (e.g., heterozygous familial
  • hypercholesterolemia or homozygous familial hypercholesterolemia
  • diseases or conditions that are caused or mediated by elevated cholesterol level include obesity, diabetes, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, diabetes, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological
  • any one of the methods featured herein further includes administering to the subject one or more cholesterol lowering agents.
  • the subject has been treated with one or more cholesterol lowering agents prior to administering a compound of the present invention (e.g., at least one compound of Formula I, such as at least one of compounds 1 -44 of Table 1 ), or a pharmaceutically acceptable salt, solvate or composition thereof.
  • a compound of the present invention e.g., at least one compound of Formula I, such as at least one of compounds 1 -44 of Table 1
  • treatment e.g., prior treatment
  • a lipase inhibitor administered prior to, concurrent with, or after administering one or more compounds of the present invention
  • a lipase inhibitor an 3-hydroxy-3-methyl-glutaryl- coenzyme A (HMG CoA) reductase inhibitor, an HMG CoA synthase inhibitor, an ATP citrate lyase inhibitor, a LDLR degradation inhibitor, a cholesterylester transfer protein (CETP) inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase or cyclase inhibitor or a combination of both, a microsomal triglyceride transfer protein (MTP) inhibitor, an Apolipoprotein B (ApoB) secretion inhibitor, a proprotein convertase subtilisin kexin type 9 (PCSK9) gene expression inhibitor, an anti-PCSK9 antibody, a PCSK9
  • the cholesterol lowering agent e.g., cholesterol lowering agent that can be administered prior to, concurrent with, or after administering one or more compounds of the present invention
  • the cholesterol lowering agent is one or more of atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin,
  • the cholesterol lowering agent (e.g., cholesterol lowering agent that can be administered prior to, concurrent with, or after administering one or more compounds of the present invention) is a cholesterol lowering agent listed in Table 3.
  • the cholesterol lowering agent e.g., cholesterol lowering agent that can be administered prior to, concurrent with, or after administering one or more compounds of the present invention
  • is a statin e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin
  • any one of the methods featured herein further includes administering to the subject an agent that increases bioavailability and/or slows metabolism of the one or more compounds of the present invention (e.g., one or more compounds of Formula I, such as one or more of compounds 1-44 of Table 1 ), or a pharmaceutically acceptable salt, solvate or composition thereof.
  • agent e.g., agent that increases bioavailability and/or slows metabolism of the one or more compounds of the present invention
  • agent is an inhibitor of at least one isoform of cytochrome P450 (CYP450), such as an inhibitor of CYP1 A2, CYP2d6, CYP2C9, CYP2C19 or CYP3A4.
  • CYP450 cytochrome P450
  • such agent e.g., agent that increases bioavailability and/or slows metabolism of the one or more compounds of the present invention
  • agent is an inhibitor of CYP3A4 (e.g., nefidipine or ritonavir).
  • any one of the methods featured herein further includes administering to the subject one or more cholesterol lowering agents, such as one or more statins (e.g., one or more statins listed in Table 3, such as Atorvastatin
  • CYP450 enzymes e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir)).
  • LDLR expression e.g., mRNA expression and/or protein expression
  • LDLR activity in a cell (e.g., a hepatic cell) by contacting the cell with an effective amount of at least one compound of the present invention (e.g., at least one compound of Formula I, such as at least one of compounds 1-44 of Table 1 ), or a pharmaceutically acceptable salt, solvate or composition thereof.
  • at least one compound of the present invention e.g., at least one compound of Formula I, such as at least one of compounds 1-44 of Table 1
  • a pharmaceutically acceptable salt, solvate or composition thereof e.g., a pharmaceutically acceptable salt, solvate or composition thereof.
  • the method further includes contacting the cell with one or more additional cholesterol lowering agents (e.g., one or more of a lipase inhibitor, an HMG CoA reductase inhibitor, an HMG CoA synthase inhibitor, an ATP citrate lyase inhibitor, a LDLR degradation inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase or cyclase inhibitor or a combination of both, a MTP inhibitor, an ApoB secretion inhibitor, a PCSK9 gene expression inhibitor, an anti-PCSK9 antibody, a PCSK9 mRNA silencer, a fibrate, a niacin or a combination of niacin with a statin, an ion-exchange resin, an ACAT inhibitor and a bile acid sequestrant, an HMG-
  • the cholesterol lowering agent is one or more of atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, pitavastatin, ezetimibe, a combination of ezetimibe and simvastatin, gemfibrozil, fenfibrate, clofibrate, cholestyramine, colestipol, colesevelam, alirocumab, evolocumab, inclisiran, AT04A, lomitapide, or mipomersen.
  • the cholesterol lowering agent is a cholesterol lowering agent listed in Table 3.
  • the cholesterol lowering agent is a statin (e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin
  • statin e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin
  • the method further includes contacting the cell with an agent that increases bioavailability and/or slows metabolism of the one or more compounds of the present invention (e.g., one or more compounds of Formula I, such as one or more of compounds 1 -44 of Table 1 ), or a pharmaceutically acceptable salt, solvate or composition thereof.
  • agent e.g., agent that increases bioavailability and/or slows metabolism of the one or more compounds of the present invention
  • CYP450 such as an inhibitor of CYP1A2, CYP2d6, CYP2C9, CYP2C19 or CYP3A4.
  • agent e.g., agent that increases bioavailability and/or slows metabolism of the one or more compounds of the present invention
  • CYP3A4 e.g., nefidipine or ritonavir
  • the method further includes contacting the cell with one or more cholesterol lowering agents, such as one or more statins (e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin
  • statins e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin
  • CYP450 enzymes e.g., Zocor®, or Pitavastatin (Livalo®)
  • CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4 e.g., nefidipine and ritonavir
  • CYP3A4 e.g., nefidipine and ritonavir
  • the cell is in a subject.
  • the subject has been diagnosed with or is predisposed to (e.g., at a risk of developing) a disease or condition that is caused or mediated by elevated cholesterol level (e.g., an elevated cholesterol associated disease, such as atherosclerosis,
  • hypercholesterolemia e.g., heterozygous familial hypercholesterolemia or homozygous familial hypercholesterolemia
  • hypertriglyceridemia diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure).
  • At least one compound of the present invention e.g., at least one compound of Formula I, such as at least one of compounds 1-44 of T able 1
  • a pharmaceutically acceptable salt or solvate thereof for the
  • elevated cholesterol level e.g., an elevated cholesterol associated disease, such as atherosclerosis, hypercholesterolemia (e.g., heterozygous familial hypercholesterolemia or homozygous familial hypercholesterolemia)
  • hypertriglyceridemia diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure) in a subject.
  • At least one compound of the present invention e.g., at least one compound of Formula I, such as at least one of compounds 1 -44 of Table 1
  • a pharmaceutically acceptable salt or solvate thereof for use in: (i) lowering cholesterol in a subject or a cell; (ii) inducing expression and/or activity of LDLR in a subject or a cell; and/or (iii) treating, reducing one or more symptoms of, delaying the onset of and/or reducing the likelihood of occurrence of a disease or condition that is caused or mediated by elevated cholesterol level (e.g., an elevated cholesterol associated disease, such as atherosclerosis, hypercholesterolemia (e.g., heterozygous familial hypercholesterolemia or homozygous familial hypercholesterolemia),
  • elevated cholesterol level e.g., an elevated cholesterol associated disease, such as atherosclerosis, hypercholesterolemia (e.g., heterozygous familial hypercholesterolemia or homozygous familial hypercholesterol
  • hypertriglyceridemia diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure) in a subject.
  • the subject is a mammal (e.g., a human).
  • the disease or condition that is caused or mediated by elevated cholesterol level is atherosclerosis, hypercholesterolemia (e.g., heterozygous familial hypercholesterolemia or homozygous familial hypercholesterolemia), hypertriglyceridemia, diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure.
  • hypercholesterolemia e.g., heterozygous familial hypercholesterolemia or homozygous familial hypercholesterolemia
  • hypertriglyceridemia diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure.
  • the disease or condition that is caused or mediated by elevated cholesterol level is atherosclerosis.
  • the disease or condition that is caused or mediated by elevated cholesterol level is hypercholesterolemia (e.g., heterozygous familial hypercholesterolemia or homozygous familial hypercholesterolemia).
  • acyl represents a hydrogen or an alkyl group, as defined herein that is attached to a parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e. , a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl.
  • exemplary unsubstituted acyl groups include from 1 to 6, from 1 to 1 1 1 , or from 1 to 21 carbons.
  • alkyl refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms).
  • An alkylene is a divalent alkyl group.
  • Ci- 6 alkyl as used herein means saturated monovalent hydrocarbon radicals having straight or branched moieties and containing from 1 to 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.
  • alkenyl refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
  • alkynyl refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
  • amino represents -N(R N1 )2, wherein each R N1 is, independently, H, OH, NO2, N(R N2 )2, S0 2 0R N2 , S0 2 R N2 , SOR N2 , an /V-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited R N1 groups can be optionally substituted; or two R N1 combine to form an alkylene or heteroalkylene, and wherein each R N2 is, independently, H, alkyl, or aryl.
  • the amino groups of the invention can be an unsubstituted amino (i.e. , -NH 2 ) or a substituted amino (i.e., -N(R N1 ) 2 ).
  • aryl refers to an aromatic mono- or
  • polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring examples include, but are not limited to, phenyl, naphthyl, 1 ,2,3,4- tetrahydronaphthyl, 1 ,2-dihydronaphthyl, indanyl, and 1H- indenyl.
  • arylalkyl represents an alkyl group substituted with an aryl group.
  • exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as Ci- 6 alkyl Ce-io aryl, C M O alkyl Ce-io aryl, or Ci- 2 o alkyl Ce-io aryl), such as, benzyl and phenethyl.
  • the akyl and the aryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • cyano represents a -CN group.
  • Carbocyclyl refers to a non-aromatic C3-12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms.
  • Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals.
  • cycloalkyl refers to a saturated, non-aromatic, monovalent mono- or polycarbocyclic radical of three to ten, preferably three to six carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.
  • halogen means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.
  • heteroalkyl refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • heteroalkyl groups are an“alkoxy” which, as used herein, refers alkyl-O- (e.g., methoxy and ethoxy).
  • a heteroalkylene is a divalent heteroalkyl group.
  • heteroalkenyl refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkenyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkenyl groups.
  • heteroalkenyl groups are an“alkenoxy” which, as used herein, refers alkenyl-O-.
  • a heteroalkenylene is a divalent heteroalkenyl group.
  • heteroalkynyl refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkynyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkynyl groups.
  • heteroalkynyl groups are an“alkynoxy” which, as used herein, refers alkynyl-O-.
  • a heteroalkynylene is a divalent heteroalkynyl group.
  • heteroaryl refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, and S, with the remaining ring atoms being C.
  • One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group.
  • heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.
  • heteroarylalkyl represents an alkyl group substituted with a heteroaryl group.
  • exemplary unsubstituted heteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as Ci- 6 alkyl C2-9 heteroaryl, C1 -10 alkyl C2-9 heteroaryl, or C1-20 alkyl C2-9 heteroaryl).
  • the akyl and the heteroaryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • heterocyclyl denotes a mono- or polycyclic radical having 3 to 12 atoms having at least one ring containing one, two, three, or four ring heteroatoms selected from N, O or S, wherein no ring is aromatic.
  • heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1 ,3-dioxanyl.
  • heterocyclylalkyl represents an alkyl group substituted with a heterocyclyl group.
  • exemplary unsubstituted heterocyclylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1 -6 alkyl C2-9 heterocyclyl, C1-10 alkyl C2-9 heterocyclyl, or C1 -20 alkyl C2-9 heterocyclyl).
  • the akyl and the heterocyclyl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • hydroxyl represents an -OH group.
  • V-protecting group represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used /V-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3 rd Edition (John Wiley & Sons, New York, 1999).
  • /V-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4- chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl, and p- toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl, p
  • cyclopentyloxycarbonyl adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and
  • benzyloxymethyl and silyl groups, such as trimethylsilyl.
  • Preferred /V-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl,
  • nitro represents an -NO2 group.
  • thiol represents an -SH group.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified.
  • Substituents include, for example: aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl,
  • aryl e.g., substituted and unsubstituted phenyl
  • carbocyclyl e.g., substituted and unsubstituted cycloalkyl
  • halogen e.g., fluoro
  • hydroxyl hydroxyl
  • heteroalkyl e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy
  • heteroaryl e.g., substituted and unsubstituted phenyl
  • heterocyclyl amino (e.g., Nhh or mono- or dialkyl amino), azido, cyano, nitro, or thiol.
  • Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)).
  • Compounds of the invention can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of
  • optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography
  • Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms.
  • Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon.
  • the appropriate technique and/or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art.
  • Racemate or “racemic mixture” means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.
  • “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R,” “S,” “S * ,” mecanic CjS M anc
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • the stereochemistry of a disclosed compound is named or depicted by structure
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9%) by weight relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure.
  • the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure.
  • Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers.
  • the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure.
  • diastereomer When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure. Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer. Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer.
  • diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers.
  • the invention embraces all of these forms.
  • solvate means a pharmaceutically acceptable solvate form of a compound of the present invention that retains the biological effectiveness of such compound.
  • solvates include, but are not limited to, compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.
  • DMSO dimethylsulfoxide
  • ethyl acetate acetic acid
  • ethanolamine or mixtures thereof.
  • one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate.
  • more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate.
  • solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non-hydrate form of the compounds.
  • a "pharmaceutically acceptable salt” as used herein means a salt that retains the biological effectiveness of the free acids and bases of the specified derivative, containing pharmacologically acceptable anions or cations, and is not biologically or otherwise undesirable.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and
  • bicarbonate bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1 , 4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne-1 ,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, y-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate,
  • naphthalene-2-sulfonate nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phospate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, teoclate, tosylate, triethiodode, valerate salts, and cations, such as sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, among others.
  • terapéuticaally effective amount means an amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate or composition thereof, that, when administered to a subject (e.g., a mammal) in need of such treatment, is sufficient to effect treatment, as defined herein.
  • pharmaceutically acceptable formulation means a combination of a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, and a carrier, diluent, excipients, and/or adjuvants that are compatible with a compound of the present invention, and is not deleterious to the recipient thereof.
  • Pharmaceutical formulations can be prepared by procedures known to those of ordinary skill in the art.
  • the compounds of the present invention can be formulated with common excipients, diluents, carriers, or adjuvants, and formed into tablets, capsules, and the like.
  • excipients, diluents, carriers, and adjuvants that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as
  • magnesium stearate and solid polyethylene glycols and also, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethyleneglycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol, liposomes and wool fat.
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such
  • Final pharmaceutical forms may be pills, tablets, powders, lozenges, sachets, cachets, or sterile packaged powders, and the like, depending on the type of excipient used. Additionally, it is specifically contemplated that pharmaceutically acceptable formulations of the present invention can contain more than one active ingredient.
  • such formulations may contain more than one compound according to the present invention.
  • such formulations may contain one or more compounds of the present invention and one or more additional hypocholesterolemic agents.
  • a pharmaceutically acceptable formulation may also include but is not limited to compounds, other than the compounds of formula I, having a structure such that, upon administration to a recipient or patient, a compound of this invention, active metabolite or residue thereof is directly or indirectly provided.
  • elevated cholesterol associated disease refers to a disease or condition that is caused or mediated by elevated cholesterol level (e.g., cholesterol level higher than that in a reference subject, such as a healthy subject).
  • elevated cholesterol associated disease can be caused by cellular and/or organ dysfunction stemming from elevated cholesterol level.
  • elevated cholesterol associated disease examples include, but are not limited to atherosclerosis, hypercholesterolemia (e.g., heterozygous familial hypercholesterolemia or homozygous familial hypercholesterolemia), hypertriglyceridemia, diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, and congestive heart failure.
  • hypercholesterolemia e.g., heterozygous familial hypercholesterolemia or homozygous familial hypercholesterolemia
  • hypertriglyceridemia diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease, and congestive heart failure.
  • One or more elevated cholesterol associated diseases can be
  • the term“elevated cholesterol level” refers to cholesterol level (e.g., cholesterol level in blood) that is higher in a subject (e.g., a human with an elevated cholesterol associated disease) by 5% or more (e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more)) compared to a healthy control (e.g., a healthy human).
  • a healthy control e.g., a healthy human
  • Elevated cholesterol level in a subject can be reduced by one or more compounds, compositions, and methods described herein.
  • hypercholesterolemia refers to a condition that is caused or mediated by the presence of high levels of cholesterol in the blood. It is an elevated cholesterol associated disease that is characterized by high blood lipids and hyperlipoproteinemia or elevated levels of lipoproteins in the blood. Familial hypercholesterolemia is the familial or inherited form of hypercholesterolemia, and is characterized by high cholesterol levels, specifically, very high levels of low-density lipoprotein (LDL) in the blood and early cardiovascular disease. Familial
  • hypercholesterolemia is caused by mutation in the gene for the LDL receptor (LDLR), which is involved in passing LDL from the body.
  • LDLR LDL receptor
  • mutations in other genes e.g., PCSK9 and the gene for Apolipoprotein B (ApoB)
  • Heterozygous familial hypercholesterolemia is familial hypercholesterolemia that is inherited from one parent
  • homozygous familial hypercholesterolemia familial hypercholesterolemia that is inherited from both parents.
  • Hypercholesterolemia e.g., familial hypercholesterolemia, such as heterozygous familial hypercholesterolemia and homozygous familial hypercholesterolemia
  • coronary artery disease includes atherosclerotic plaque prevention, regression, or stabilization, vulnerable plaque prevention, regression, or stabilization, vulnerable plaque area reduction, arterial calcification (e.g., calcific aortic stenosis), increased coronary artery calcium score, dysfunctional vascular reactivity, vasodilation disorders, coronary artery spasm, first myocardial infarction, myocardia re-infarction, ischemic cardiomyopathy, stent restenosis, PTCA restenosis, arterial restenosis, coronary bypass graft restenosis, vascular bypass restenosis, decreased exercise treadmill time, angina pectoris/chest pain, unstable angina pectoris, exertional dyspnea, decreased exercise capacity, ischemia, silent ischemia, increased severity and frequency of ischemic symptoms, and reperfusion after thrombolytic therapy for acute myocardial infarction.
  • arterial calcification e.g., calcific aortic stenosis
  • hypertension is selected, but not limited to the group consisting of lipid disorders with hypertension, systolic hypertension, and diastolic hypertension.
  • peripheral vascular disease is selected, but not limited to the group consisting of peripheral vascular disease and claudication.
  • diabetes refers to any of a number of hypothalamic hormones
  • diabetogenic states including type I diabetes, type II diabetes, Syndrome X,
  • Metabolic syndrome lipid disorders associated with insulin resistance, impaired glucose tolerance, non-insulin dependent diabetes, microvascular diabetic complications, reduced nerve conduction velocity, reduced or loss of vision, diabetic retinopathy, increased risk of amputation, decreased kidney function, kidney failure, insulin resistance syndrome, pluri-metabolic syndrome, central adiposity
  • diabetes (visceral)(upper body), diabetic dyslipidemia, decreased insulin sensitization, diabetic retinopathy/neuropathy, diabetic nephropathy/micro and macro angiopathy and micro/macro albuminuria, diabetic cardiomyopathy, diabetic gastroparesis, obesity, increased glycosylated hemoglobin (including HbA1 C), impaired glucose control, impaired renal function (e.g., requiring dialysis, or end stage) and impaired hepatic function (e.g., mild, moderate, or severe).
  • impaired renal function e.g., requiring dialysis, or end stage
  • impaired hepatic function e.g., mild, moderate, or severe.
  • “Metabolic syndrome,” also known as“SyndromeX,” refers to a common clinical disorder that is characterized by the presence of increased insulin
  • concentration in association with other disorders including visceral obesity, hyperlipidemia, dyslipidemia, hyperglycemia, hypertension, and potentially hyperuricemis and renal dysfunction.
  • treat refers to any treatment of a disease or condition that is caused or mediated by elevated cholesterol level (e.g., an elevated cholesterol associated disease) in a subject, such as a mammal, particularly a human, and include: (i) preventing the disease or condition from occurring in a subject that may be predisposed to (e.g., at a risk of developing) the condition or reducing the likelihood of occurrence of the disease or condition in a subject that may be predisposed to (e.g., at a risk of developing) the condition, such that the treatment constitutes prophylactic treatment for the pathologic condition; (ii) modulating or inhibiting the disease or condition, i.e., arresting its development; (iii) delaying the onset of the disease or condition; (iv) relieving or reducing the disease or condition, i.e., causing regression of the disease or condition; or (v) relieving, reducing and/or alleviating the disease or condition or the symptoms resulting from the disease or
  • the terms“increase,”“increasing,”“induce” or“inducing” and “decrease,”“decreasing,”“reduce” or’’reducing” refer to modulating resulting in, respectively, greater or lesser amounts, of function, expression level, occurrence, or activity of a metric relative to a reference. For example, subsequent to
  • cholesterol level may reduce or decrease in a subject by at least 5% or more (e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more)) relative to cholesterol level prior to administration of the compounds.
  • 5% or more e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more
  • one or more symptoms of an elevated cholesterol associated disease may reduce or decrease in a subject by at least 5% or more (e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more)) relative to the symptoms of the disease prior to administration of the compounds.
  • 5% or more e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more)
  • the likelihood or chance of occurrence of an elevated cholesterol associated disease may reduce or decrease in a subject by at least 5% or more (e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more)) relative to the likelihood or chance of occurrence of the disease in a reference subject (e.g., a subject to whom the compounds has not been administered).
  • a reference subject e.g., a subject to whom the compounds has not been administered.
  • LDLR expression e.g., mRNA and/or protein expression
  • LDLR activity may increase or induce in a subject by at least 5% or more (e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more)) relative to LDLR expression and/or LDLR activity prior to administration of the compounds.
  • 5% or more e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more
  • the metric is measured subsequent to administration at a time that the administration has had the recited effect, e.g., at least one week, one month, 3 months, or 6 months, after a treatment regimen has begun.
  • the term“reducing” is used interchangeably with the term“decreasing” herein.
  • the term“increasing” is used interchangeably with the term“inducing” herein.
  • Delaying the onset refers to delaying or postponing the onset, start or occurrence of a condition relative to a reference. For example, subsequent to administration of one or more compounds described herein, the onset, start, or occurrence of an elevated cholesterol associated disease in a subject may be delayed or postponed by at least 1 month or more (e.g., 1 month, 2 months,
  • a subject predisposed to an elevated cholesterol associated disease may have a higher (e.g., at least 5% or more (e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20- 80%, or between 20-100% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more)) risk, chance, or likelihood of developing the elevated cholesterol associated disease compared to a reference (e.g., a subject who is not predisposed to the disease).
  • a reference e.g., a subject who is not predisposed to the disease.
  • co-administration refers to the administration of a combination of at least a first agent and a second agent or two or more agents according to the present invention. Such co-administration can be performed such that two or multiple agents are part of the same composition or part of the same unitary dosage form. Co-administration also includes administering a first agent and a second agent, or more than two agents separately and as part of the same therapeutic regimen. The agents, if administered separately, need not necessarily be administered at essentially the same time, although they can be if so desired.
  • co-administration includes, for example, administering a first agent and a second agent as separate dosages or dosage forms, but at the same time. Co administration also includes separate administration at different times and in any order.
  • Co-administration can include administration of more than one compound featured herein.
  • Co-administration can also include administration of one or more of the featured compounds and an additional cholesterol lowering agent.
  • compound of the present invention refers to any of the above- mentioned compounds, as well as those in the Examples that follow, and include those generically described or those described as species. These terms also refers to pharmaceutically acceptable salts or solvates of these compounds.
  • Such compounds include compounds of Formula I (e.g., compounds 1 -44 of Table 1 ).
  • FIG. 1A and FIG. 1 B are graphs depicting half maximal effective
  • FIG. 2 is a graph depicting pharmacokinetic profile of Compound III in
  • the present disclosure describes picolinic acid derived compounds of Formula I (e.g., any one of compounds 1-44 of Table 1 ), pharmaceutically acceptable salts or solvates thereof, and pharmaceutical compositions including one or more of the compounds. Also featured herein are methods of synthesis or manufacture of the compounds and use of the compounds in inducing low density lipoprotein receptor (LDLR) expression and activity. Compounds featured herein are useful for lowering total circulating cholesterol, and treating, reducing the symptoms of, reducing the likelihood of occurrence of, delaying the onset of, or delaying the progression of diseases that are associated with elevated cholesterol.
  • LDLR low density lipoprotein receptor
  • a compound featured herein may have the structure of formula (I):
  • Y is OR 3 ;
  • Z is H, optionally substituted Ci- 6 alkyl, or -CFhOR ⁇ L is optionally substituted C1 -6 alkyl or optionally substituted C1-6 heteroalkyl;
  • Ri is H, -OH, optionally substituted C1-6 alkyl, optionally substituted C5-10 heterocycle, optionally substituted Ob-io aryl, or optionally substituted C5-10 heteroaryl;
  • R 2 is N R5R6 or OR5;
  • each of R3 and R4 is, independently, H, optionally substituted C1-6 alkyl, optionally substituted C1-6 fluoroalkyl, benzyl, phenyl, or optionally substituted C5-10 heterocycle; or R 3 and R 4 combine to form an optionally substituted heterocycle,
  • R 5 IS H, optionally substituted C1 -6 alkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C1-6 fluoroalkyl, optionally substituted C1-6 alkyl Ce-io aryl, or optionally substituted C5-10 heterocycle;
  • R6 is H or optionally substituted C1 -6 alkyl
  • R 5 is methyl, propyl, cyclopropyl
  • R6 is methyl
  • X is * 3 ⁇ 4 ⁇ Rs .
  • R5 is -CF3.
  • X is cyano
  • Y is OH.
  • Z is methyl or -
  • Y is OR 3 .
  • Z is -CH 2 OR 4 .
  • R 3 and R 4 combine to form an optionally substituted heterocycle.
  • the optionally substituted heterocycle is
  • a compound of Formula I may have the structure of any one of compounds 1-44 of Table 1 , or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention also describes methods of synthesizing the compounds that are featured herein (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ).
  • the first approach starts from pyridoxine that is modified to produce intermediate I using methodologies described in Paul et al. (J Med Chem 1977, 20:745).
  • Compound I is etherified by Williamson synthesis approach using methane sulphonyl chloride to generate intermediate II.
  • the resulting mesylate/alkyl halide is then converted to intermediate Ilia, lllb or lllc with the appropriate nucleophiles; alcoholate, phenolate, thiolate, amine or heterocyclic anions.
  • intermediate I is converted in the presence of a non-nucleophilic base to an alcoholate and reacted in situ to an electrophile such as an alkyl halide.
  • the alkyl halide is a para-methoxy benzyl halide which generates the useful intermediate compound.
  • This compound can be further modified to IV by heating with an excess alkylamine.
  • the resulting amide may be deprotected from its acetonide form with formic acid to the form V.
  • the useful compounds are formed from the starting material pyridoxine VI by first protecting the compound as acetonide VII, followed by etherification to VIII through a procedure similar to Scheme 1 .
  • the resulting compound is sequentially oxidized (IX, X, XI) to compounds of form Ilia. These compounds are then deprotected from the acetonide XII and the 4 position reduced to a methyl group by catalytic hydrogenation of the corresponding acetate. Reacting the ester with an amine either neat or in an appropriate solvent gives compound XIII.
  • Compound I can be oxidized selectively to compound XIV using manganese dioxide and further reacted with carbanions such as -CF 3 to trifluoroalcohols XV.
  • compositions contemplated herein include at least one compound of the present invention, and pharmaceutically acceptable salts, solvate or composition thereof, with a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethyleneglycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
  • Compounds of the present invention that are basic may be prepared as a salt using suitable methods known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; and the like, or with an organic acid, such as acetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidyl acid, such as glucuronic acid or galacturonic acid; alpha-hydroxy acid, such as citric acid or tartaric acid; amino acid, such as aspartic acid or glutamic acid; aromatic acid, such as benzoic acid or cinnamic acid; sulfonic acid, such as p-toluenesulfonic acid or methanesulfonic acid; and the like.
  • an inorganic acid such as hydrochloric acid; hydro
  • Basic compounds of the present invention can form a variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is common practice to first isolate the compound of the present invention as a pharmaceutically unacceptable salt and then convert to a free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol.
  • Compounds of the present invention that are acidic may be prepared as a salt using suitable methods known in the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine;
  • ammonia primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • Acidic compounds of the present invention can form base salts with various pharmacologically acceptable cations.
  • such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts, which can be prepared using conventional techniques.
  • the chemical bases suitable as reagents in preparing the pharmaceutically acceptable base salts of this invention are those that form non-toxic base salts with the acidic compounds of the present invention.
  • Such non-toxic base salts include those derived from such
  • salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • a pharmaceutical composition including at least one of the compounds of the present invention is administered in a pharmaceutically acceptable formulation prepared by combining a therapeutically effective amount of the compound with one or more pharmaceutically suitable carriers including diluents, excipients and auxiliaries that facilitate processing of the active compounds into a pharmaceutically acceptable formulation.
  • Carriers employed may be either solid or liquid.
  • Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like.
  • Exemplary liquid carriers are syrup, peanut oil, olive oil, water, and the like.
  • inventive compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate, or the like.
  • time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate, or the like.
  • Further additives or excipients may be added to achieve the desired formulation properties.
  • a bioavailability enhancer such: as Labrasol®, Gelucire®, or the like, or formulators, such as CHIC (carboxy- methylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol), may be added.
  • CHIC carboxy- methylcellulose
  • PG propyleneglycol
  • Gelucire® a semi-solid vehicle that protects active ingredients from light, moisture and oxidation, may be added, e.g., when preparing a capsule formulation.
  • a solid carrier the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge.
  • the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.
  • a liquid carrier the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non- aqueous liquid suspension.
  • the inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g., parenteral or oral
  • a pharmaceutically acceptable salt of a compound of the present invention may be dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 M solution of succinic acid or citric acid.
  • the agent may be dissolved in a suitable co solvent or combinations of co-solvents.
  • suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin, and the like in concentrations ranging from 0-60% of the total volume.
  • a compound of the present invention is dissolved in DMSO and diluted with water.
  • the composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
  • compositions for oral use can be obtained using a solid excipient in an admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients include: fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
  • polyvinylpyrrolidone PVP
  • disintegrating agents such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the pharmaceutical compositions comprising the compounds of the present invention may also contain suitable solid- or gel-phase carriers or excipients. These carriers and excipients may provide marked improvement in the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium, phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Furthermore, additives or excipients such as Gelucire®, Capryol®, Labrafil®, Labrasol®, Lauroglycol®, Plurol®, Peceol®, Transcutol®, and the like may be used. Further, the pharmaceutical composition may be incorporated into a skin patch for delivery of the drug directly onto the skin.
  • suitable solid- or gel-phase carriers or excipients may provide marked improvement in the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium, phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as poly
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral bioavailability, increase solubility to allow administration by injection, alter metabolism, or alter rate of excretion ( Pharmacokinetic Optimization in Drug
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir, and are preferably administered orally or parenterally.
  • the pharmaceutical compositions of this invention may contain any conventional non toxic pharmaceutically acceptable carriers, adjuvants or vehicles.
  • parenteral or“parenterally” as used herein includes sub-cutaneous, intra- cutaneous, intra-venous, intra-muscular, intra-articular, intra-synovial, intra-sternal, intra-thecal, intra-lesional and intracranial injection or infusion techniques.
  • compositions of the invention may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solutions.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • Pharmaceutical compositions of the invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspension and solutions. In the case of tablets for oral administration, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, and/or coloring agents may be added.
  • compositions of the invention may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient that is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • the actual dosages of the compounds of this invention will vary according to the particular compound being used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated.
  • compounds of Formula I such as any one of compounds 1-44 of Table 1
  • those skilled in the art using conventional dosage-determination tests in view of the experimental data for a given compound may ascertain optimal dosages for a given set of conditions.
  • an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals, preferably between 0.01 and about 25 mg/kg body weight per day, and more preferably between about 0.5 and about 25 mg/kg body weight per day of the active ingredient compound are useful in the prevention and treatment of elevated cholesterol, including high circulating LDL.
  • the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in an amount of about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 500 mg, or from about 50 mg to about 500 mg, or from about 100 mg to about 500 mg.
  • the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in an amount of about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 500 mg, or from about 50 mg to about 500 mg, or from about 100 mg to about 500 mg.
  • the pharmaceutically acceptable formulations of the present invention may contain a compound of the present
  • pharmaceutically acceptable salt or solvate thereof in an amount from about 0.5 w/w % to about 95 w/w %, or from about 1 w/w % to about 95 w/w %, or from about 1 w/w % to about 75 w/w %, or from about 5 w/w % to about 75 w/w %, or from about 10 w/w % to about 75 w/w %, or from about 10 w/w % to about 50 w/w %.
  • compositions of this invention will be
  • a typical preparation will contain from about 5% to about 75% active compound (w/w). Preferably, such preparations contain from about 20% to about 50% active compound.
  • the compound, composition or combination of this invention may be administered if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been reduced or alleviated to the desired level, treatment should cease, at least in principle. Patients may, however, require intermittent treatment on a long-term basis, upon any recurrence of disease symptoms, especially for high levels of cholesterol. As the skilled artisan will appreciate, lower or higher doses than those recited above may be required.
  • Specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease (e.g., elevated cholesterol associated disease), the patient’s disposition to the disease and the judgment of the treating physician.
  • the severity and course of the disease e.g., elevated cholesterol associated disease
  • the particular pharmaceutical formulation, the dosage, and the number of doses given per day to a mammal requiring such treatment are all choices within the knowledge of one of ordinary skill in the art and can be determined without undue experimentation.
  • the compounds of this invention are also useful as commercial reagents that effectively lower circulating cholesterol.
  • the compounds of this invention, and their derivatives may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications.
  • the compounds of the present invention can be used alone (monotherapy) or administered in combination with one or more additional cholesterol lowering agents for the treatment of high blood lipids associated diseases, such as diseases or conditions that are caused or mediated by elevated cholesterol level (e.g., elevated cholesterol associated diseases), including, but not limited to, atherosclerosis, hypercholesterolemia (heterozygous and homozygous familial hypercholesterolemia included), hypertriglyceridemia, diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure in a subject (e.g., a mammal, such as a human).
  • a subject e.g., a mammal, such as a human.
  • the compounds of this invention may be administered in combination with other cholesterol lowering agents (e.g., additional cholesterol lowering agents) that target other steps in the cholesterol metabolism.
  • cholesterol lowering agents e.g., additional cholesterol lowering agents
  • these agents include, but are not limited to: a lipase inhibitor, an 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor, an HMG CoA synthase inhibitor, an ATP citrate lyase inhibitor, a LDLR degradation inhibitor, a cholesterylester transfer protein (CETP) inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase or cyclase inhibitor or a combination of both, a microsomal triglyceride transfer protein (MTP) inhibitor, an Apolipoprotein B (ApoB) secretor a lip
  • one or more compounds of this invention may be administered in combination with one or more cholesterol lowering agents listed in Table 3, such as statins (e.g., Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin (Zocor®), or Pitavastatin (Livalo®)).
  • statins e.g., Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin (Zocor®), or Pitavastatin (Livalo®)
  • statins e.g., Atorvastatin (Lipitor®), Fluvastatin
  • Combination therapies according to this invention may exert an additive or combined effect on reduction of elevated cholesterol because each therapeutic agent of the combination acts on a different site of cholesterol metabolism.
  • the use of such combination therapies may also advantageously enable a reduction in the dosage of each cholesterol lowering agent, compared to administration of either agent alone as a monotherapy, while providing an equivalent or better therapeutic or prophylactic effect.
  • Administration of lower doses of each therapeutic agent often reduces or even eliminates side effects or toxicity relative to monotherapy.
  • combination therapies may reduce the potential for the development of undesired side effects to the agents administered compared to monotherapy.
  • One or more cholesterol lowering agents e.g., one or more cholesterol lowering agents listed in Table 3, such as statins (e.g., Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®),
  • statins e.g., Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®
  • Simvastatin (Zocor®), or Pitavastatin (Livalo®)) may be administered to a subject (e.g., a mammal, such as a human (e.g., a human patient)) prior to, concurrent with, or following the administration of one or more compounds of Formula I (e.g., any one of compounds 1-44 of Table 1 ) featured herein.
  • a subject e.g., a mammal, such as a human (e.g., a human patient)
  • one or more compounds of Formula I e.g., any one of compounds 1-44 of Table 1
  • compositions of this invention may include a combination of cholesterol lowering agent of this invention (e.g., one or more compounds of Formula I, such as any one of compounds 1-44 of Table 1 , featured herein) and another therapeutic or prophylactic agent, such as one or more additionalcholesterol lowering agents (e.g., one or more cholesterol lowering agents listed in Table 3, such as statins (e.g., Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin
  • statins e.g., Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin
  • a subject e.g., a mammal, such as a human (e.g., a human patient)
  • one or more cholesterol lowering agents e.g., one or more cholesterol lowering agents listed in Table 3, such as statins (e.g., Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®),
  • statins e.g., Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®
  • Simvastatin (Zocor®), or Pitavastatin (Livalo®)) prior to administering one or more compounds of the present invention (e.g., at least one compound of Formula I, such as any one of compounds 1 -44 of Table 1 ), or a pharmaceutically acceptable salt, solvate or composition thereof.
  • compounds of the present invention e.g., at least one compound of Formula I, such as any one of compounds 1 -44 of Table 1
  • a pharmaceutically acceptable salt, solvate or composition thereof e.g., a pharmaceutically acceptable salt, solvate or composition thereof.
  • treatment e.g., prior treatment
  • one or more cholesterol lowering agents e.g., one or more cholesterol lowering agents listed in Table 3, such as statins (e.g., Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin (Zocor®), or Pitavastatin (Livalo®))
  • statins e.g., Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin (Zocor®), or Pitavastatin (Livalo®)
  • statins e.g., Atorvastatin (L
  • Some embodiments of the current disclosure describe methods of inducing LDLR expression (e.g., mRNA expression and/or protein expression) and/or LDLR activity in a cell (e.g., a hepatic cell), such as a cell in a subject (e.g., a hepatic cell in a subject) by contacting the cell with an effective amount of at least one compound of the present invention (e.g., at least one compound of Formula I, such as at least one of compounds 1 -44 of Table 1 ), or a pharmaceutically acceptable salt, solvate or composition thereof.
  • a cell e.g., a hepatic cell
  • an effective amount of at least one compound of the present invention e.g., at least one compound of Formula I, such as at least one of compounds 1 -44 of Table 1
  • a pharmaceutically acceptable salt, solvate or composition thereof e.g., a pharmaceutically acceptable salt, solvate or composition thereof.
  • Such methods may further include contacting the cell with one or more additional cholesterol lowering agents (e.g., one or more of a lipase inhibitor, an HMG CoA reductase inhibitor, an HMG CoA synthase inhibitor, an ATP citrate lyase inhibitor, a LDLR degradation inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase or cyclase inhibitor or a combination of both, a MTP inhibitor, an ApoB secretion inhibitor, a PCSK9 gene expression inhibitor, an anti-PCSK9 antibody, a PCSK9 mRNA silencer, a fibrate, a niacin or a combination of niacin with a statin, an ion-exchange resin, an ACAT inhibitor and a bile acid sequestrant, an HMG-CoA reduc
  • methods of inducing LDLR expression e.g., mRNA expression and/or protein expression
  • LDLR activity in a cell may include contacting the cell with an effective amount of at least one compound of the present invention (e.g., at least one compound of Formula I, such as at least one of compounds 1-44 of Table 1 , or a pharmaceutically acceptable salt, solvate or composition thereof) in combination with one or more cholesterol lowering agents listed in Table 3, such as statins (e.g., Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin
  • statins e.g., Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (P
  • suitable for combination therapies with the compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • suitable for treating subjects e.g., mammals, such as humans (e.g., human patients) prior to administration of compounds of this invention are listed in Table 3 below.
  • compounds of the present invention may be administered in combination with an additional agent or pharmaceutical composition that increases the bioavailability or slows the metabolism of the compounds.
  • agents or pharmaceutical composition that increases the bioavailability or slows the metabolism of the compounds.
  • compositions that may increase the bioavailability or slow the metabolism of the compounds featured herein include inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzymes, preferably inhibitors of CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4.
  • Suitable agents that may be used to inhibit CYP 3A4 include, but are not limited to, nefidipine and ritonavir.
  • compounds of the present invention may be administered in combination with one or more inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir).
  • CYP450 enzymes preferably inhibitors of CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir).
  • compounds of the present invention may be administered in combination with one or more cholesterol lowering agents (e.g., cholesterol lowering agents listed in Table 3, such as statins (e.g., Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin (Zocor®), or Pitavastatin (Livalo®))) and one or more agents that increase the bioavailability or slow the metabolism of the compounds (e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (
  • Such combinations may be administered such that a compound or compounds of the present invention are present in a single formulation or in the form of separate formulations that may be administered sequentially with an appropriate period of time in between or simultaneously.
  • the choice of whether to include the compound or compounds of the present invention in the same formulation as the additional agent or agents is within the knowledge of one of ordinary skill in the art.
  • Some embodiments of the current disclosure describe methods of inducing LDLR expression (e.g., mRNA expression and/or protein expression) and/or LDLR activity in a cell (e.g., a hepatic cell), such as a cell in a subject (e.g., a hepatic cell in a subject) by contacting the cell with an effective amount of at least one compound of the present invention (e.g., at least one compound of Formula I, such as at least one of compounds 1 -44 of Table 1 ), or a pharmaceutically acceptable salt, solvate or composition thereof.
  • Such methods may further include contacting the cell with an additional agent or pharmaceutical composition that increases the bioavailability or slows the metabolism of the compounds.
  • Agents or pharmaceutical compositions that may increase the bioavailability or slow the metabolism of the compounds featured herein include inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4.
  • Suitable agents that may be used to inhibit CYP3A4 include, but are not limited to, nefidipine and ritonavir. Therapeutic effects
  • compositions and methods for reducing cholesterol level e.g., cholesterol level in blood
  • a subject e.g., a human, such as a human with an elevated cholesterol associated disease
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • additional agents e.g., cholesterol lowering agents (e.g., cholesterol lowering agents listed in Table 3) and/or agents that increase the bioavailability or slow the metabolism of the compounds.
  • cholesterol level (e.g., cholesterol level in blood) can be reduced in a subject (e.g., a human, such as a human with an elevated cholesterol associated disease) in need thereof by administering to the subject one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1 -44 of T able 1 ) in combination with one or more statins (e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin (Zocor®), or Pitavastatin (Livalo®)).
  • statins e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL
  • cholesterol level e.g., cholesterol level in blood
  • a subject e.g., a human, such as a human with an elevated cholesterol associated disease
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1 -44 of T able 1
  • agents that increase the bioavailability or slow the metabolism of the compounds e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1 A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir)).
  • cholesterol level e.g., cholesterol level in blood
  • a subject e.g., a human, such as a human with an elevated cholesterol associated disease
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • statins e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®),
  • Rosuvastatin (Crestor®), Simvastatin (Zocor®), or Pitavastatin (Livalo®)) and one or more agents that increase the bioavailability or slow the metabolism of the compounds (e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir)).
  • CYP450 enzymes e.g., CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir)).
  • the subject may have elevated cholesterol level, such as cholesterol level (e.g., cholesterol level in blood) that is higher by 5% or more (e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more)) compared to a healthy control (e.g., a healthy human).
  • cholesterol level e.g., cholesterol level in blood
  • 5% or more e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more
  • a healthy control e.g., a healthy human
  • One or more compounds of the invention can reduce cholesterol level (e.g., cholesterol level in blood, such as elevated cholesterol level in blood) in a subject (e.g., a subject with an elevated cholesterol associated disease) by at least 5% or more (e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100%) relative to cholesterol level prior to administration of the compounds, or relative to cholesterol level in a reference subject to whom the compounds have not been administered (e.g., a subject with the elevated cholesterol associated disease to whom the compounds have not been administered).
  • cholesterol level e.g., cholesterol level in blood, such as elevated cholesterol level in blood
  • a subject e.g., a subject with an elevated cholesterol associated disease
  • one or more compounds of the invention can reduce cholesterol level in a subject (e.g., a subject with an elevated cholesterol associated disease) by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more relative to cholesterol level prior to administration of the compounds, or relative to cholesterol level in a reference subject to whom the compounds have not been administered (e.g., a subject with the elevated cholesterol associated disease to whom the compound have not been administered).
  • a subject e.g., a subject with an elevated cholesterol associated disease
  • compositions and methods for inducing LDLR expression e.g., mRNA and/or protein expression
  • a cell such as a cell in a subject (e.g., a human, such as a human with an elevated cholesterol associated disease) or a cell in a culture (e.g., a culture generated from a human (e.g., a human with an elevated cholesterol associated) sample, or a repository of human sample) by contacting the cell with one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) alone (monotherapy) or in combination (combination therapy) with one or more additional agents (e.g., cholesterol lowering agents and/or agents that increase the bioavailability or slow the metabolism of the compounds).
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • additional agents e.g., cholesterol lowering agents and/or agents that increase the bioavailability or slow the metabolism of
  • LDLR expression (e.g., mRNA and/or protein expression) can be induced in a cell, such as a cell in a subject (e.g., a human, such as a human with an elevated cholesterol associated disease) or a cell in a culture (e.g., a culture generated from a human (e.g., a human with an elevated cholesterol associated) sample, or a repository of human sample) by contacting the cell with one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1 -44 of Table 1 ) in combination with one or more statins (e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL),
  • statins e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL),
  • LDLR expression e.g., mRNA and/or protein expression
  • a cell such as a cell in a subject (e.g., a human, such as a human with an elevated cholesterol associated disease) or a cell in a culture (e.g., a culture generated from a human (e.g., a human with an elevated cholesterol associated) sample, or a repository of human sample) by contacting the cell with one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1 -44 of Table 1 ) in combination with one or more agents that increase the bioavailability or slow the metabolism of the compounds (e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1A2, CYP2d6, CYP2C9, CYP2C19 and
  • LDLR expression e.g., mRNA and/or protein expression
  • a cell such as a cell in a subject (e.g., a human, such as a human with an elevated cholesterol associated disease) or a cell in a culture (e.g., a culture generated from a human (e.g., a human with an elevated cholesterol associated) sample, or a repository of human sample) by contacting the cell with one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) in combination with one or more statins (e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®),
  • statins e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor
  • Rosuvastatin (Crestor®), Simvastatin (Zocor®), or Pitavastatin (Livalo®)) and one or more agents that increase the bioavailability or slow the metabolism of the compounds (e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir)).
  • CYP450 enzymes e.g., CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir)).
  • One or more compounds of the invention can induce LDLR expression (e.g., mRNA and/or protein expression) in a cell by at least 5% or more (e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100%) relative to LDLR expression prior to contacting with the compounds, or relative to LDLR expression in a reference cell, such as a control cell that has not been contacted with the compounds.
  • LDLR expression e.g., mRNA and/or protein expression
  • a reference cell such as a control cell that has not been contacted with the compounds.
  • one or more compounds of the invention can induce LDLR expression in a cell by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more relative to LDLR expression prior to contacting with the compounds, or relative to LDLR expression in a reference cell, such as a control cell that has not been contacted with the compounds.
  • compositions and methods for inducing LDLR activity in a cell such as a cell in a subject (e.g., a human, such as a human with an elevated cholesterol associated disease) or a cell in a culture (e.g., a culture generated from a human (e.g., a human with an elevated cholesterol associated) sample, or a repository of human sample) by contacting the cell with one or more compounds of this invention (e.g., compounds of Formula I, such as compounds 1- 44 of Table 1 ) alone (monotherapy) or in combination (combination therapy) with one or more additional agents (e.g., cholesterol lowering agents and/or agents that increase the bioavailability or slow the metabolism of the compounds).
  • a cell in a subject e.g., a human, such as a human with an elevated cholesterol associated disease
  • a culture e.g., a culture generated from a human (e.g., a human with an elevated cholesterol associated) sample, or a repository of human sample
  • LDLR activity can be induced in a cell, such as a cell in a subject (e.g., a human, such as a human with an elevated cholesterol associated disease) or a cell in a culture (e.g., a culture generated from a human (e.g., a human with an elevated cholesterol associated) sample, or a repository of human sample) by contacting the cell with one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1 -44 of Table 1 ) in combination with one or more statins (e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin (Zocor®), or Pitavastatin (Livalo®)).
  • LDLR activity can be induced in a cell, such as a cell in a subject (e.g., a human, such as a human with an elevated cholesterol associated disease) or a cell in a culture (e.g., a culture generated from a human (e.g., a human with an elevated cholesterol associated) sample, or a repository of human sample) by contacting the cell with one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1 -44 of Table 1 ) in combination with one or more agents that increase the bioavailability or slow the metabolism of the compounds (e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir)).
  • a cell in a subject
  • LDLR activity can be induced in a cell, such as a cell in a subject (e.g., a human, such as a human with an elevated cholesterol associated disease) or a cell in a culture (e.g., a culture generated from a human (e.g., a human with an elevated cholesterol associated) sample, or a repository of human sample) by contacting the cell with one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1 -44 of T able 1 ) in combination with one or more statins (e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®), Rosuvastatin (Crestor®), Simvastatin (Zocor®), or Pitavastatin
  • statins e.g., one
  • CYP450 enzymes e.g., CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir)
  • CYP3A4 e.g., nefidipine and ritonavir
  • One or more compounds of the invention can induce LDLR activity in a cell by at least 5% or more (e.g., between 5- 20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100%) relative to LDLR activity prior to contacting with the compounds, or relative to LDLR activity in a reference cell, such as a control cell that has not been contacted with the compounds.
  • a reference cell such as a control cell that has not been contacted with the compounds.
  • compounds of the invention can induce LDLR activity in a cell by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more relative to LDLR activity prior to contacting with the compounds, or relative to LDLR activity in a reference cell, such as a control cell that has not been contacted with the compounds.
  • compositions and methods for treating one or more elevated cholesterol associated disease e.g., atherosclerosis,
  • hypercholesterolemia (heterozygous and homozygous familial hypercholesterolemia included), hypertriglyceridemia, diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure) in a subject in need thereof (e.g., a human, such as a human with an elevated cholesterol associated disease) by administering to the subject one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) alone (monotherapy) or in combination (combination therapy) with one or more additional agents (e.g., cholesterol lowering agents and/or agents that increase the bioavailability or slow the metabolism of the compounds).
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • additional agents e.g
  • one or more elevated cholesterol associated disease e.g., atherosclerosis, hypercholesterolemia (heterozygous and homozygous familial hypercholesterolemia included), hypertriglyceridemia, diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure
  • a subject in need thereof e.g., a human, such as a human with an elevated cholesterol associated disease
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • statins e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (
  • one or more elevated cholesterol associated disease e.g., atherosclerosis, hypercholesterolemia (heterozygous and homozygous familial hypercholesterolemia included), hypertriglyceridemia, diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure
  • a subject in need thereof e.g., a human, such as a human with an elevated cholesterol associated disease
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • agents that increase the bioavailability or slow the metabolism of the compounds e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1
  • one or more elevated cholesterol associated disease e.g., atherosclerosis, hypercholesterolemia (heterozygous and homozygous familial hypercholesterolemia included), hypertriglyceridemia, diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure
  • a subject in need thereof e.g., a human, such as a human with an elevated cholesterol associated disease
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • statins e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Meva
  • Simvastatin (Zocor®), or Pitavastatin (Livalo®)
  • agents that increase the bioavailability or slow the metabolism of the compounds e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1 A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir)).
  • compositions and methods for reducing one or more symptoms or indications of an elevated cholesterol associated disease e.g., atherosclerosis, hypercholesterolemia (heterozygous and homozygous familial hypercholesterolemia included), hypertriglyceridemia, diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure
  • a subject e.g., a human, such as a human with an elevated cholesterol associated disease
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • additional agents e.g., cholesterol lowering agents and/or agents that increase the bioavailability or slow the metabolism of the compounds.
  • one or more symptoms or indications of an elevated cholesterol associated disease can be reduced in a subject in need thereof (e.g., a human, such as a human with an elevated cholesterol associated disease) by administering to the subject one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) in combination with one or more statins (e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL
  • one or more symptoms or indications of an elevated cholesterol associated disease can be reduced in a subject in need thereof (e.g., a human, such as a human with an elevated cholesterol associated disease) by administering to the subject one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) in combination with one or more agents that increase the bioavailability or slow the metabolism of the compounds
  • one or more symptoms or indications of an elevated cholesterol associated disease can be reduced in a subject in need thereof (e.g., a human, such as a human with an elevated cholesterol associated disease) by administering to the subject one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) in combination with one or more statins (e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL),
  • statins e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL)
  • One or more compounds of the invention can reduce one or more symptoms or indications of an elevated cholesterol associated disease in a subject (e.g., a subject with the elevated cholesterol associated disease) by at least 5% or more (e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100%) relative to the symptoms or indications prior to administration of the compounds, or relative to the symptoms or indications in a reference subject to whom the compounds have not been administered (e.g., a subject with the elevated cholesterol associated disease to whom the compounds have not been administered).
  • a subject e.g., a subject with the elevated cholesterol associated disease
  • monotherapy or in combination therapy can reduce one or more symptoms or indications of an elevated cholesterol associated disease in a subject (e.g., a subject with the elevated cholesterol associated disease) by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more relative to the symptoms or indications prior to administration of the compounds, or relative to the symptoms or indications in a reference subject to whom the compounds have not been administered (e.g., a subject with the elevated cholesterol associated disease to whom the compounds have not been administered).
  • a subject e.g., a subject with the elevated cholesterol associated disease
  • compositions and methods for delaying the onset of an elevated cholesterol associated disease e.g., atherosclerosis,
  • hypercholesterolemia (heterozygous and homozygous familial hypercholesterolemia included), hypertriglyceridemia, diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure) in a subject (e.g., a human, such as a human predisposed to an elevated cholesterol associated disease) by administering to the subject one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) alone (monotherapy) or in combination (combination therapy) with one or more additional agents (e.g., cholesterol lowering agents and/or agents that increase the bioavailability or slow the metabolism of the compounds).
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • additional agents e.g.
  • the onset of an elevated cholesterol associated disease can be delayed in a subject in need thereof (e.g., a human, such as a human with an elevated cholesterol associated disease) by administering to the subject one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) in combination with one or more statins (e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL), Lovastatin
  • statins e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL), Lovastatin
  • the onset of an elevated cholesterol associated disease can be delayed in a subject in need thereof (e.g., a human, such as a human with an elevated cholesterol associated disease) by administering to the subject one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) in combination with one or more agents that increase the bioavailability or slow the metabolism of the compounds (e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP450 enzymes, preferably inhibitors of CYP450 enzymes, preferably inhibitors of CYP450 enzymes, preferably inhibitors of CYP450 enzymes, preferably inhibitors of CYP450 enzymes, preferably inhibitors of CYP450 enzymes, preferably inhibitors of CYP450 enzymes, preferably inhibitors of CYP450 enzymes, preferably inhibitors of CYP450 enzymes, preferably inhibitors of CYP450 enzymes, preferably inhibitors of CYP450 enzymes
  • an elevated cholesterol associated disease e.g., atherosclerosis, hypercholesterolemia (heterozygous and homozygous familial hypercholesterolemia included), hypertriglyceridemia, diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure
  • a subject in need thereof e.g., a human, such as a human with an elevated cholesterol associated disease
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • statins e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL), Lovastatin
  • Simvastatin (Zocor®), or Pitavastatin (Livalo®)
  • agents that increase the bioavailability or slow the metabolism of the compounds e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1 A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir)).
  • One or more compounds of the invention can delay the onset of an elevated cholesterol associated disease in a subject (e.g., a human, such as a human predisposed to an elevated cholesterol associated disease) by at least 1 month or more (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months,
  • compositions and methods for reducing the likelihood or chance of occurrence of an elevated cholesterol associated disease e.g., atherosclerosis, hypercholesterolemia (heterozygous and homozygous familial hypercholesterolemia included), hypertriglyceridemia, diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure
  • a subject e.g., a human, such as a human predisposed to an elevated cholesterol associated disease
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • additional agents e.g., cholesterol lowering agents and/or agents that increase the bioavailability or slow the metabolism of the compounds.
  • the likelihood or chance of occurrence of an elevated cholesterol associated disease e.g., atherosclerosis, hypercholesterolemia
  • hypertriglyceridemia diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure
  • a subject in need thereof e.g., a human, such as a human with an elevated cholesterol associated disease
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • statins e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (Mevacor®, Altoprev®), Pravastatin (Pravachol®)
  • the likelihood or chance of occurrence of an elevated cholesterol associated disease can be reduced in a subject in need thereof (e.g., a human, such as a human with an elevated cholesterol associated disease) by administering to the subject one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) in combination with one or more agents that increase the bioavailability or slow the metabolism of the compounds
  • the likelihood or chance of occurrence of an elevated cholesterol associated disease can be reduced in a subject in need thereof (e.g., a human, such as a human with an elevated cholesterol associated disease) by administering to the subject one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) in combination with one or more statins (e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL),
  • statins e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL)
  • One or more compounds of the invention can reduce the likelihood or chance of occurrence of an elevated condition or a decreased concentration of a compound in the body.
  • agents that increase the bioavailability or slow the metabolism of the compounds e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir)).
  • CYP450 enzymes e.g., CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir)
  • CYP3A4 e.g., nefidipine and ritonavir
  • a subject e.g., a human, such as a human predisposed to an elevated cholesterol associated disease
  • at least 5% or more e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100% relative to a reference subject to whom the
  • one or more compounds of the invention can reduce the likelihood or chance of occurrence of an elevated cholesterol associated disease in a subject (e.g., a human, such as a human predisposed to an elevated cholesterol associated disease) by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more relative to a reference subject to whom the compounds have not been administered (e.g., a subject predisposed to the elevated cholesterol associated disease to whom the compounds have not been administered).
  • a subject e.g., a human, such as a human predisposed to an elevated cholesterol associated disease
  • compositions and methods for delaying the progression of an elevated cholesterol associated disease e.g., atherosclerosis, hypercholesterolemia (heterozygous and homozygous familial hypercholesterolemia included), hypertriglyceridemia, diabetic complications, dyslipidemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, stroke, vascular dementia, chronic kidney disease, coronary heart disease, coronary artery disease, retinopathy, inflammation, thrombosis, peripheral vascular disease or congestive heart failure
  • a subject in need thereof e.g., a human, such as a human with an elevated cholesterol associated disease
  • compounds of this invention e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1
  • additional agents e.g., cholesterol lowering agents and/or agents that increase the bioavailability or slow the metabolism of the compounds.
  • the progression of an elevated cholesterol associated disease can be delayed in a subject in need thereof (e.g., a human, such as a human with an elevated cholesterol associated disease) by administering to the subject one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) in combination with one or more statins (e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, LescoKD XL), Lovastat
  • the progression of an elevated cholesterol associated disease can be delayed in a subject in need thereof (e.g., a human, such as a human with an elevated cholesterol associated disease) by administering to the subject one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) in combination with one or more agents that increase the bioavailability or slow the metabolism of the compounds (e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP
  • the progression of an elevated cholesterol associated disease can be delayed in a subject in need thereof (e.g., a human, such as a human with an elevated cholesterol associated disease) by administering to the subject one or more compounds of this invention (e.g., compounds of Formula I, such as any one of compounds 1-44 of Table 1 ) in combination with one or more statins (e.g., one or more statins listed in Table 3, such as Atorvastatin (Lipitor®), Fluvastatin (Lescol®, Lescol® XL), Lovastatin (M
  • Rosuvastatin (Crestor®), Simvastatin (Zocor®), or Pitavastatin (Livalo®)) and one or more agents that increase the bioavailability or slow the metabolism of the
  • compounds e.g., inhibitors of at least one isoform of CYP450 enzymes, preferably inhibitors of CYP1A2, CYP2d6, CYP2C9, CYP2C19 and CYP3A4, such as inhibitors of CYP3A4 (e.g., nefidipine and ritonavir)).
  • One or more compounds of the invention can delay the progression of an elevated cholesterol associated disease in a subject (e.g., a subject with the elevated cholesterol associated disease) by at least 5% or more (e.g., between 5-20%, between 5-50%, between 10-50%, between 10-80%, between 20-80%, or between 20-100%) relative to the progression prior to administration of the compounds, or relative to progression in a reference subject to whom the compounds have not been administered (e.g., a subject with the elevated cholesterol associated disease to whom the compounds have not been administered).
  • a subject e.g., a subject with the elevated cholesterol associated disease
  • monotherapy or in combination therapy can delay the progression of an elevated cholesterol associated disease in a subject (e.g., a subject with the elevated cholesterol associated disease) by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more relative to the progression prior to administration of the compounds, or relative to progression in a reference subject to whom the compounds have not been administered (e.g., a subject with the elevated cholesterol associated disease to whom the compounds have not been
  • Preparative chromatography was performed by flash chromatography, using silica gel 60 (EM Science) with the indicated solvent systems and positive air pressure, to allow for a proper rate of elution. Detection of the compounds was carried out by exposing eluted plates (analytical or preparative) to iodine, UV light and/or treating analytical plates with a 2% solution of p-anisaldehyde in ethanol containing 3% sulfuric acid and 1 % acetic acid, followed by heating. Alternatively, analytical plates can be treated with a 0.3% ninhydrin solution in ethanol containing 3% acetic acid and/or a CAM solution made of 20 g (NH4) q Mq7q24 and 8.3 g
  • Triethyl amine (TEA) was added and methanesulphonyl chloride added dropwise over 20 minutes.
  • TLC revealed a complete conversion of the starting material.
  • 4-fluoroindole was dissolved in tetrahydrofuran THF and potassium tert-butoxide (KOtB) was added.
  • the dichloromethane solution was evaporated without heating and the solvent replaced with THF.
  • the methyl 5- (methansulphoxymethyl)-2,2-dimethyl-4H-[1 ,3]dioxino[4,5-c]pyridine-8-carboxylate THF solution was dripped slowly over 20 minutes into the Indole solution and left to warm to room temperature (RT).
  • Example 2 The product from Example 1 was dissolved in neat cyclopropyl amine and heated to 55 °C for 12 h. TLC showed 1 product.
  • reaction was quenched carefully by adding ice-cold water to the viscous mixture at 0 °C and diluted with a saturated ammonium chloride solution followed by extraction with methylene chloride.
  • the combined organic extracts were washed with brine, dried (Na 2 S0 4 ), and
  • Trifluoroacetic anhydride (3.5 mL, 32 mmol) was added to a solution of 5-((4- methoxybenzyloxy)methyl)-2,2,8-trimethyl-4H-[1 ,3]dioxino[4,5-c]pyridine 7-oxide (5.0 g, 61 mmol) in dry CH2CI2 (200 ml) at 0 °C and stirred for 5 min. An additional amount of trifluoroacetic anhydride (10.5 mL) was added and the reaction mixture was stirred overnight at 23 °C. Then, the reaction mixture was cooled to 0 °C and MeOH (150 mL) was added while stirring was continued.
  • Methyl 3-hydroxy-4-(methyl)-5-((4-methoxybenzyloxy)methyl)picolinate 500 mg was dissolved in neat cyclopropylamine and heated to 55 °C for 12h. TLC monitoring showed complete conversion. Evaporation of the amine followed by trituration with 1 % citric acid yielded a white solid that was filtered off and dried.
  • the compound from the above example was dissolved in 90% formic acid and heated at 75 °C for 4 h.
  • the solvent was evacuated under vacuum, the residue triturated with water, and then the residue flashed chromatographed on silica gel (EtoAc eluent).
  • the solvent was evacuated and the residue crystallized.
  • the compound was synthesized using the general procedure outlined in
  • Example 25 The compound from Example 25 (65 mg) was stirred in a sealed vial containing 500 uL of cyclopropylamine at 45 °C for 48 h until completion.
  • the compound was synthesized using the general procedure outlined in
  • the compound was synthesized using the general procedure outlined in
  • Example 37 The compound from Example 37 (65 mg) was stirred in a sealed vial containing 500 uL of cyclopropylamine at 45 °C for 48 h until completion.
  • Methyl 5-(hydroxymethyl)-2,2-dimethyl-4H-[1 ,3]dioxino[4,5-c]pyridine-8- carboxylate (Paul et al., J Med Chem, 1977, 20:745) was dissolved in ethyl acetate and cooled to 0 °C. Triethyl amine (TEA) was added and methanesulphonyl chloride added dropwise over 20 minutes. TLC revealed a complete conversion of the starting material. Meanwhile, 4-trifluorphenol was dissolved in tetrahydrofuran THF and potassium tert-butoxide (KOtB) was added. The mesylate solution was evaporated without heating and the solvent replaced with DMF.
  • TAA Triethyl amine
  • KtB potassium tert-butoxide
  • Example 2 To the product of Example 2 was added trimethylsilyltrifluoromethane in THF. To the vigorously stirred mixture was then added caesium fluoride. The mixture bubbled vigorously and subsided within 1 minute. TLC showed complete conversion of the starting material. The residue after evaporation was then chromatographed on silica gel to yield a clean product.
  • Example 45 Cell culture and treatment
  • Human hepatoma cell line HepG2 was routinely cultivated in Dulbecco’s modified Eagle’s medium (DMEM; catalog no. 319-005-CL, Wisent) supplemented with 10% fetal bovine serum (FBS; catalog no. 080-350, Wisent).
  • DMEM Dulbecco’s modified Eagle’s medium
  • FBS fetal bovine serum
  • LDLR phenotypic screening of LDLR, cells were incubated overnight in conditioned media containing small molecule inducers compounds 1-32 resuspended in DMSO at concentration ranging from 10 nM to 10 mM.
  • Example 46 Western blot analysis
  • PBS phosphate-buffered saline
  • radioimmune precipitation assay buffer 50 mM Tris/HCI, pH 8.0, 1 % (v/v) Nonidet P-40, 0.5% sodium deoxycholate, 150 mM NaCI, and 0.1 % (v/v) SDS
  • a complete protease inhibitor mixture catalog no. 1 1 697 498 001 , Roche Applied Science.
  • MTT is converted to dark blue, water-insoluble MTT formazan by mitochondrial dehydrogenases present in living cells.
  • the blue crystals of MTT formazan were solubilized with 100 pL acidic isopropanol (0.06 N) and absorbance measured at a wavelength of 570 nm with background subtraction at 650 nm.
  • Arbitrary units of cell viability of a given example were determined relative to equal volume of DMSO (vehicle) for each concentration used. Results are shown in Table 4.
  • HMM human liver microsomes
  • RLM pooled male Sprague Dawley rat liver microsomes
  • NNK Sprague Dawley rat liver microsomes
  • Reactions were terminated at each time point (0, 5, 10, 20, 30, 45, and 60 min) by transferring 50 pL in a new 96-well plate and adding 100 pi of acetonitrile containing an internal standard (labetalol at 2 pM). The plates were centrifuged at 4000 rpm for 5 min, and an aliquot of supernatant was diluted with one volume of water + 0.1 % formic acid before analysis by LC-MS/MS.
  • Reference samples were also prepared at concentrations between 0.002 pM and 2 pM in buffer containing microsomes, by adding the diluted solutions of the compound to the buffer containing microsomes quenched with 2 volume of acetonitrile containing the internal standard (whereas the incubation TO is obtained by quenching the microsomes containing the compound, then adding NADPH).
  • mice For in vivo animal studies, wild-type C57BL/6 male mice ( ⁇ 25 g; obtained from Charles River Laboratories) or Golden Syrian (-120 g obtained from Envigo++) were housed in the 12 hour light/12 hour dark cycle, temperature and humidity controlled MHI animal facility. Following 5 days of acclimatization, animals were fed a chow or Western diet containing 48.5% w/w carbohydrate, 21 .2% w/w fat, 17.3% w/w protein and 0.2% w/w cholesterol (catalog no. TD.88137, Envigo) for 14 days.
  • Example 3 was mixed in either ethanol/propylene glycol/water 1 :7:8 and administered by oral gavage at 40 mg/kg/day for 10 days in mice maintained on Western diet.
  • Plasma lipoprotein cholesterol profiles were obtained from 100 pl_ of pooled plasma injected on a Superose 6 10/300 GL (catalog no. 17-5172-01 , GE Life Sciences) and eluted with PBS at a flow rate of 0.1 mL per min at 4 °C mounted on a AKTA explorer system (GE Healthcare).
  • Total cholesterol (catalog no. 439-17501 , Wako) was quantified in total plasma and in each 0.3 mL collected fractions or in-line (Lipidomics Core of The Group on Molecular and Cell Biology of Lipids, University of Alberta) according to the manufacturer’s instructions.

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Abstract

La présente invention concerne des composés de la formule (I), dans laquelle X est tel que défini ci-dessus ; Y est OR3 ; Z est H, un alkyle éventuellement substitué ou -CH2OR4; L est un alkyle ou un hétéroalkyle éventuellement substitué ; R1 est H, -OH, un alkyle, un hétérocycle, un aryle ou un hétéroaryle éventuellement substitué ; R2 est NR5R6 ou OR5 ; R3 et R4 sont chacun H ou un alkyle, un benzyle, un phényle ou un hétérocycle éventuellement substitué ; ou R3 et R4 se combinent en vue de former un hétérocycle éventuellement substitué ; R5 est H ou un alkyle, cycloalkyle, un hétéroalkyle, un alkylaryle ou un hétérocycle éventuellement substitué ; R6 est H ou un alkyle, ou des sels, des solvates ou des compositions de qualité pharmaceutique de ces derniers. Les composés de la formule (I) augmentent significativement l'expression et l'activité du récepteur de lipoprotéines de faible densité, réduisent le cholestérol circulant total et sont utiles pour traiter et retarder l'apparition de maladies associées à un taux élevé de cholestérol, tels que l'athérosclérose et l'hypercholestérolémie.
PCT/CA2020/050721 2019-05-28 2020-05-27 Dérivés d'acide picolinique et leur utilisation dans le traitement de maladies associées à un taux élevé de cholestérol Ceased WO2020237374A1 (fr)

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WO2025079125A1 (fr) * 2023-10-08 2025-04-17 Al-Zaytoonah University Of Jordan Composé carboxamide-2-picoline hybridé avec des dérivés d'anthraquinone, procédés de préparation, composition pharmaceutique le comprenant et utilisation associée

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025079125A1 (fr) * 2023-10-08 2025-04-17 Al-Zaytoonah University Of Jordan Composé carboxamide-2-picoline hybridé avec des dérivés d'anthraquinone, procédés de préparation, composition pharmaceutique le comprenant et utilisation associée

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