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WO2015196205A1 - Procédé d'utilisation de composés calcilytiques pour traiter des maladies dues à des niveaux d'insuline ou de glucose anormaux - Google Patents

Procédé d'utilisation de composés calcilytiques pour traiter des maladies dues à des niveaux d'insuline ou de glucose anormaux Download PDF

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Publication number
WO2015196205A1
WO2015196205A1 PCT/US2015/037010 US2015037010W WO2015196205A1 WO 2015196205 A1 WO2015196205 A1 WO 2015196205A1 US 2015037010 W US2015037010 W US 2015037010W WO 2015196205 A1 WO2015196205 A1 WO 2015196205A1
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WO
WIPO (PCT)
Prior art keywords
calcilytic
drug
sensing receptor
calcium sensing
subject
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2015/037010
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English (en)
Inventor
Valerie N. BABINSKY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bentley Liz
Hough Alison
Hough Tertius A
Nesbit M Andrew
Thakker Rajesh V
GlaxoSmithKline LLC
Original Assignee
Bentley Liz
Hough Alison
Hough Tertius A
Nesbit M Andrew
Thakker Rajesh V
GlaxoSmithKline LLC
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Filing date
Publication date
Application filed by Bentley Liz, Hough Alison, Hough Tertius A, Nesbit M Andrew, Thakker Rajesh V, GlaxoSmithKline LLC filed Critical Bentley Liz
Publication of WO2015196205A1 publication Critical patent/WO2015196205A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate

Definitions

  • the present disclosure relates generally to methods of treating hyperglycemia, diabetes, metabolic syndrome or symptoms thereof.
  • the method includes the step of administering a calcilytic drug to a subject presenting with glucose intolerance and/or insulin resistance.
  • Figure 1 is a graph that illustrates plasma glucose levels in Nuf mice and wild- type littermates.
  • Figure 2 is a graph that illustrates plasma insulin levels in Nuf mice and wild-type littermates.
  • Figure 3 is a graph that illustrates plasma glucose levels in Nuf mice treated with either vehicle or the calcilytic, ronacaleret.
  • the present disclosure relates to methods of treating diseases of abnormal glucose or insulin levels, including diabetes, metabolic syndrome, or symptoms thereof, including the step of administering a calcilytic drug to a subject presenting with glucose intolerance.
  • the cause of the disease may be hereditary or etiological.
  • the disease may be associated with a mutation in the calcium-sensing receptor (CaSR) or a mutation in one or more downstream participants in CaSR signaling.
  • the calcilytic drug may be administered to subjects with a gain of function mutation in either the CaSR or at least one of its downstream signaling molecules at either a reduced dose, a reduced frequency of dosing, or both relative to a subject that expresses the wild-type protein(s).
  • Types 1 and 2 diabetes and metabolic syndrome are diseases that are associated with glucose intolerance. These illnesses are accompanied by an increased risk of cardiovascular disease and other life-threatening disorders. Despite their severity, treatments for these diseases are limited.
  • the G-protein coupled calcium-sensing receptor is a pivotal regulator of extracellular calcium homeostasis.
  • Calcilytics are molecules that block CaSR signaling. They antagonize CaSR signaling by directly interacting with the CaSR.
  • the cells in which the CaSR is expressed include pancreatic beta cells, where it regulates insulin secretion in vitro. However, the role of this receptor in glucose homeostasis is unknown.
  • the method includes treatment of subjects that express either wild-type or a variant CaSR.
  • Ranges can be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as "about” that particular value in addition to the value itself. For example, if the value " 10" is disclosed, then “about 10" is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed as a range, then 11, 12, 13, and 14 are also disclosed.
  • Oral administration means administration of a therapeutic agent into the alimentary canal through the mouth.
  • Oral compositions of the calcilytics for use in the disclosed methods may be formulated as syrups, tablets, capsules, and lozenges as well as other formulations known in the art.
  • Parenteral administration means administration of a therapeutic agent via intravenous injection or infusion, intravascular injection, subcutaneous injection, intraperitoneal injection, or intramuscular injection.
  • Wild-type iittermate as used herein, means a !ittermate in a mouse litter that includes Nuf mouse littermates and which does not include a calcium-sensing receptor gene with the activating CaSR mutation, Leu723Gln, in its genome.
  • calcilytic compounds refer to compounds able to inhibit calcium receptor activity, including receptor antagonists.
  • the ability of a compound to "inhibit calcium receptor activity” means that the compound causes a decrease in one or more calcium receptor activities evoked by extracellular Ca 2+ .
  • the use of calcilytic compounds to inhibit calcium receptor activity and/or achieve a beneficial effect in a patient is known, for example, from U.S. Patent Nos. 6,395,919, 7,202,261, and 7,829,594, each of which is incorporated herein in its entirety.
  • [Ca 2+ ] 0 the concentration of extracellular ionized calcium(Ca 2+ ) (hereinafter, [Ca 2+ ] 0 ) is typically under rigid homeostatic control and regulates various processes such as blood clotting, nerve and muscle excitability, and proper bone formation. Serum Ca 2+ concentration is kept within the relatively narrow range of about 1.1-1.4 mmol/L. Extracellular Ca 2+ inhibits the secretion of parathyroid hormone (“PTH”) from parathyroid cells, and stimulates secretion of calcitonin from C-cells. The CaSR enables certain specialized cells to respond to changes in [Ca 2+ ] 0 . These specialized cells include pancreatic beta cells which secrete insulin.
  • PTH parathyroid hormone
  • insulin secretion is modified in response to variations in [Ca 2+ ] 0 . This is thought to occur through a mechanism that involves cell-cell communication between pancreatic beta cells that occurs in response to local increases in [Ca 2+ ] 0 rather than changes in systemic calcium concentrations.
  • Calcilytic drugs through their ability to inhibit CaSR activity, thereby cause a decrease in one or more CaSR activities evoked by extracellular Ca 2+ .
  • Such compounds are useful in the treatment of various disease states characterized by abnormal levels of one or more components, e.g., polypeptides such as hormones, enzymes or growth factors, the expression and/or secretion of which is regulated or affected by activity at the CaSR.
  • Abnormal calcium homeostasis may be characterized by one or more of the following activities: an abnormal increase or decrease in serum calcium; an abnormal increase or decrease in urinary excretion of calcium; an abnormal increase or decrease in bone calcium levels (for example, as assessed by bone mineral density measurements); an abnormal absorption of dietary calcium; an abnormal increase or decrease in the production and/or release of messengers which affect serum calcium levels, such as PTH and calcitonin; and an abnormal change in the response elicited by messengers which affect serum calcium levels.
  • CaSR inhibitors are important in the pharmacotherapy of diseases associated with abnormally low levels of serum calcium such as hypoparathyroidism and idiopathic hypercalciuria and may be used to treat other disorders of bone and mineral metabolism/homeostasis such as osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, and osteoporosis.
  • disorders associated with abnormal serum glucose levels are associated with elevated calcium levels and/or excessive CaSR signaling.
  • diseases associated with abnormal serum glucose levels are associated with elevated calcium levels and/or excessive CaSR signaling.
  • diseases associated with abnormal serum glucose levels are associated with elevated calcium levels and/or excessive CaSR signaling.
  • diseases associated with abnormal serum glucose levels are associated with elevated calcium levels and/or excessive CaSR signaling.
  • these disorders may be treated by administering drugs that antagonize the CaSR.
  • disorders include, but are not limited to, type 1 diabetes, type 2 diabetes, gestational diabetes, pre-diabetes, metabolic syndrome, and others associated with glucose intolerance and/or insulin resistance.
  • Calcilytic compounds that may be used in the disclosed methods include those of Formula (I), shown below.
  • R groups are alkyl or hydrogen.
  • Compound 1 has the structure of Formula (I) where Ri, R 2 , R 3 , and R 5 are H, and R 4 is a nitrile group.
  • Compound 1 has the chemical name of (R)-3-(4-cyano-3-(3-(l-(2,3-dihydro-lH-inden-2-yl)-2-methylpropan-2-ylamino)-2- hydroxypropoxy) phenyl) propanoic acid, the structure of which is shown below.
  • the calcilytic drug of the disclosed methods is an ester, having the structure of Formula (I) where Ri is an alkyl group such as methyl or ethyl.
  • Ri is an alkyl group such as methyl or ethyl.
  • Compound 1 may be a prodrug.
  • the Ri group may be involved in the conversion of the prodrug to the active compound.
  • Such embodiments have the structure of Formula (II), shown below.
  • Compound 2 has the structure of Formula (II) in which Ri is an ethyl and has the chemical name of ethyl (R)-3-(4- cyano-3-(3-((l-(2,3-dihydro-lH-inden-2-yl)-2-methylpropan-2-yl)amino)-2- hydroxypropoxy)phenyl)propanoate.
  • the calcilytic compound used in the disclosed methods comprises ronacaleret, which has the chemical name of 3-[3-[(2R)-3-[[l-(2,3-dihydro-lH- inden-2-yl)-2-methylpropan-2-yl]amino]-2-hydroxypropoxy]-4,5-difluorophenyl]propanoic acid, the structure of which is shown below.
  • Compound 1 and ronacaleret include a carboxylic acid moiety. Such acids may be isolated or prepared in a salt form.
  • a pharmaceutically acceptable salt includes a salt formed from an inorganic acid such as a hydrobromide or hydrochloride salt. The stoichiometry of the salt may be, for example, a hemi-salt, or a mono- or di-salt or tri-salt.
  • the present disclosure includes calcilytic compounds which may be in a prodrug form.
  • Prodrugs of the calcilytic compounds described herein readily undergo chemical changes under physiological conditions to provide the calcilytic compounds.
  • Certain calcilytic drugs can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Some calcilytic drugs may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are within the scope of the present disclosure.
  • Calcilytic drugs encompassed by the present disclosure include all isotopes of atoms occurring therein. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. As is evident from the structure of Formulae (I) and (II), some calcilytic drugs possess chiral or asymmetric carbon atoms (optical centers); the racemates, diastereomers, geometric isomers and individual optical isomers are all intended to be encompassed within the scope of the present invention.
  • the methods disclosed herein comprise the step of oral, parenteral, topical (transdermal), oral inhalation, or transmucosal administration of the calcilytic.
  • the calcilytic is administered orally.
  • the calcilytic is administered parenterally.
  • Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/kg, and preferably from 0.1 to 50 mg/kg body weight, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 n g to 100 mg/kg body weight, of a compound of Formula(I) or Formula (II).
  • a topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I) or Formula (II).
  • the active ingredient may be administered from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
  • treatment of a disease includes, but is not limited to prevention, retardation and prophylaxis of the disease.
  • the method may be used to treat diseases of abnormal glucose or insulin levels, including diabetes, metabolic syndrome, or symptoms thereof in patients that possess a genetic mutation that results in a modified CaSR protein.
  • the modified CaSR may exhibit increased sensitivity to extracellular calcium relative to the wild-type CaSR.
  • the modified CaSR protein may comprise a missense mutation, a deletion in the CaSR protein, or both.
  • CaSR protein mutations that may be present in patients suffering from diseases which may be treated by administering calcilytic drugs according to the methods disclosed herein include one or more of Lys29Glu, Leul25Pro, Cysl31Trp, Glu228Ala, Asp410Glu, Leu723Glu, Ala840Val, Ala843Glu and any of the 90 unique mutations (86 missense, 3 frame-shifts, 1 deletion) identified to date (Hannan et al. 2012 Human Molecular Genetics 21 :2768-2778, which is herein incorporated by reference).
  • An effective amount of a calcilytic drug for treatment of hyperglycemia, diabetes, metabolic syndrome, or symptoms thereof would have one or more of the following effects: reduced serum calcium, reduced urinary calcium excretion, increased serum parathyroid hormone, reduced plasma glucose, and increased plasma insulin.
  • Amino alcohol calcilytic drugs interact with the CaSR within the transmembrane domain of the receptor. Mutations in the CaSR that are located near the amino alcohol calcilytic binding site include Leu723Glu, Ala840Val, and Ala843Glu. Because patients with altered plasma glucose and/or insulin levels may express a CaSR gene with a mutation that results in an altered CaSR protein, the amount of calcilytic drug required to reduce elevated plasma glucose, raise abnormally low plasma insulin levels, and mitigate related symptoms as discussed herein, may be altered relative to that necessary to cause these effects in an individual that expresses the wild-type CaSR.
  • the disclosed method is used to treat a patient that possesses a genetic mutation that results in a gain of function in the CaSR protein.
  • the disclosed method may be used to treat such a patient by administering a lower dose of calcilytic drug relative to that required to treat an individual that expresses the wild-type CaSR.
  • the dosing frequency that is effective to mitigate these symptoms in a patient that expresses an altered CaSR protein may be altered relative to that necessary to cause the same or similar effects in an individual that expresses the wild-type CaSR.
  • the dosing frequency is reduced in a patient that expresses an altered CaSR protein that includes a gain of function mutation relative to that necessary to cause the same or similar effects in an individual that expresses the wild-type CaSR.
  • both the effective dose and effective dosing schedule may be altered in an individual that expresses a modified CaSR protein.
  • both the effective dose and the effective dosing frequency necessary to cause the aforementioned effects may be reduced when treating an individual that expresses a CaSR protein with a gain of function mutation as compared to an individual that expresses the wild-type CaSR.
  • the step of administering a calcilytic drug to a patient may alter the expression of genes downstream of CaSR signaling to levels that occur in the presence of lowered extracellular calcium. Consequently, the disclosed method includes the step of administering a calcilytic drug wherein serum parathyroid hormone and/or fibroblast growth factor-23 levels are elevated.
  • the methods of treating subjects with the calcilytic drugs as described herein include administration by different routes, including, without limitation, intravenous, intravascular, intraperitoneal, subcutaneous, intramuscular, topical (transdermal), transmucosal, and oral administration.
  • oral administration the compounds may be formulated into oral dosage forms such as, for example, liquid-filled capsules, or liquid preparations such as syrups, elixirs, or concentrated drops.
  • the calcilytic drugs may be formulated in isotonic liquid solutions, such as in physiologically compatible buffers or carbohydrate solutions.
  • Intravenous, subcutaneous, intraperitoneal, and intramuscular doses may be given by means of a bolus injection. Alternatively the intravenous or intraperitoneal dose may be given by continuous infusion over a period of time.
  • Plasma glucose and insulin concentrations were measured using an Analox glucose analyser and Milliplex mouse immunoassay, respectively.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé pour traiter l'intolérance au glucose et/ou la résistance à l'insuline et des symptômes associés par administration d'un médicament calcilytique à un sujet le nécessitant.
PCT/US2015/037010 2014-06-20 2015-06-22 Procédé d'utilisation de composés calcilytiques pour traiter des maladies dues à des niveaux d'insuline ou de glucose anormaux Ceased WO2015196205A1 (fr)

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US201462015270P 2014-06-20 2014-06-20
US62/015,270 2014-06-20

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070155819A1 (en) * 2004-02-06 2007-07-05 Marquis Robert W Jr Calcilytic compounds
US20090163589A1 (en) * 2002-11-26 2009-06-25 Smithkline Beecham. Corp. Calcilytic Compounds
US20110229587A1 (en) * 2009-09-24 2011-09-22 Algaecal Distribution Inc. Calcium Supplements for the Treatment of Diabetes
US20130190407A1 (en) * 1991-08-23 2013-07-25 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130190407A1 (en) * 1991-08-23 2013-07-25 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US20090163589A1 (en) * 2002-11-26 2009-06-25 Smithkline Beecham. Corp. Calcilytic Compounds
US20070155819A1 (en) * 2004-02-06 2007-07-05 Marquis Robert W Jr Calcilytic compounds
US20110229587A1 (en) * 2009-09-24 2011-09-22 Algaecal Distribution Inc. Calcium Supplements for the Treatment of Diabetes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAKAMURA, A ET AL.: "Loss-of-Function and Gain-of-Function Mutations of Calcium-Sensing Receptor: Functional Analysis and the Effect of Allosteric Modulators NPS R-568 and NPS- 2143", J CLIN ENDOCRINOL METAB ., vol. 98, no. 10, 2013, pages E1692 - E1701, XP055246027 *

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