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WO2010098125A1 - Composé agoniste partiel des récepteurs des rétinoïdes x - Google Patents

Composé agoniste partiel des récepteurs des rétinoïdes x Download PDF

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WO2010098125A1
WO2010098125A1 PCT/JP2010/001317 JP2010001317W WO2010098125A1 WO 2010098125 A1 WO2010098125 A1 WO 2010098125A1 JP 2010001317 W JP2010001317 W JP 2010001317W WO 2010098125 A1 WO2010098125 A1 WO 2010098125A1
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compound
rxr
ipr
amino
nicotinic acid
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加来田博貴
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Okayama University NUC
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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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a partial agonist compound of a retinoid X receptor (RXR), which is a nuclear receptor, and more specifically, a novel compound that moderately activates various nuclear receptors composed of RXR and heterodimer About. Furthermore, it relates to its action.
  • RXR retinoid X receptor
  • RXR is one of the nuclear receptors and regulates transcription in a ligand-dependent manner.
  • 9-cis retinoic acid sputum (Fig. 1 (1)) is known as an endogenous RXR agonist, which also activates the retinoic acid receptor (RAR).
  • RAR retinoic acid receptor
  • LGD1069 (FIG. 1 (2)), the first synthetic RXR selective agonist, has been approved in the United States for the treatment of recurrent skin invasive T-cell lymphoma (FDA, U.S.A.).
  • FDA skin invasive T-cell lymphoma
  • U.S.A. recurrent skin invasive T-cell lymphoma
  • RXR is involved in gene expression, but it is known that it acts by forming a heterodimer with its own homodimer or other nuclear receptors (PPAR, LXR, FXR, RAR, TR, etc.) Yes. In the functional expression of these nuclear receptors, RXR plays a role in stabilizing the binding between the target gene and the heterodimer by constructing a dimer structure with the heterodimer partner. The presence of the RXR agonist further stabilizes this dimer structure and exerts a synergistic effect on the activity of the heterodimer partner agonist.
  • RXR-RAR heterodimer the activation of RXR-RAR heterodimer is enhanced by the presence of RXR agonist in the presence of a low concentration of RAR agonist that does not have differentiation-inducing ability due to insufficient RAR activation ability, and differentiation induction It is known that the effect is recognized.
  • the partners that RXR forms heterodimers are classified as “permissive” partners and “non-permissive partners”.
  • the former is a nuclear receptor capable of activating heterodimers with an RXR agonist alone, such as PPAR, LXR, FXR.
  • the latter is a nuclear receptor in which heterodimer is not activated by an RXR agonist alone, and RAR, VDR, TR, etc. correspond to this.
  • RXR is a very attractive molecular target, but a common problem with existing RXR agonists is an increase in blood triglycerides (TG) (Non-Patent Documents 1 and 2). RXR agonists activate RXR-LXR, and TG rises by activation of LXR (Non-patent Document 3). As a solution, RXR agonists have the ability to selectively activate RXR-PPAR heterodimers. The compound which has is made
  • RXR agonists developed so far including LGD1069, are full agonists that fully activate RXR at high concentrations (Non-Patent Documents 6 and 7). Full agonists can cause homeostasis failure due to excessive receptor activity.
  • RXR partial agonists Several compounds are currently reported as RXR partial agonists (FIGS. 1 (4)-(8)).
  • Compound (4) in FIG. 1 is a derivative (Non-patent Document 8) in which LGD1069 (FIG. 1 (2)) is the lead and the linker moiety is converted to sulfone (Non-Patent Document 8).
  • EC 50 is about 2 ⁇ M for each subtype.
  • UVI3007 (Fig. 1 (5)) uses RXR agonist CD3254 as a lead and converts the methyl group located at the ortho position of the linker to a methoxy group, thereby creating a partial agonist with E max suppressed to about 70%. ing.
  • Non-Patent Documents 9 and 10 the knowledge that E max is decreased by introducing a sulfonamide group into the linker site (Non-Patent Documents 9 and 10) has also been obtained.
  • 9-cis retinoic acid (Fig. 1 (1)) is the lead, and by changing the fat-soluble part, it leads to the creation of a compound with less effective effect.
  • Non-Patent Document 4 Although these compounds have been reported as RXR partial agonists, their usefulness such as drug efficacy has not been reported.
  • Non-Patent Document 11 a rexinoid compound having an alkoxy group, which is a low fat-soluble RXR ⁇ selective agonist.
  • An object of the present invention is to provide a safer RXR agonist (rexinoid) compound with reduced fat solubility.
  • the present inventors predicted that the high lipophilicity of many RXR ligands was highly attributable to the tetramethyltetrahydronaphthyl ring, which is a fat-soluble structure, so that the lipophilic site was converted to a structure having a polar group.
  • the inventors succeeded in synthesizing an RXR partial agonist that has reduced fat solubility and can exhibit an excellent pharmacological effect, thereby completing the present invention.
  • R 1 is (CH 2 ) n R 3
  • R 2 is iPr
  • R 3 is OMe, Me, Ph, or COPh
  • n is an integer from 1 to 5
  • a retinoid X receptor partial agonist compound that is either: (A) a compound in which R 1 is iPr and R 2 is O-iPr in general formula I; (B) a compound of the general formula I, wherein R 1 is iBu and R 2 is O-iBu; (C) In the general formula I, a compound in which R 1 is iPr and R 2 is OMe, (D) a compound of the general formula I, wherein R 1 is (CH 2 ) n R 3 , R 2 is iPr, R 3 is Ph, and n is 3.
  • (E) a compound of the general formula I, wherein R 1 is (CH 2 ) n R 3 , R 2 is iPr, R 3 is COPh, and n is 1.
  • R 1 is (CH 2 ) n R 3 , R 2 is iPr, R 3 is Me, and n is 5, or
  • R 1 is (CH 2 ) n R 3 , R 2 is iPr, R 3 is OMe and n is 3. 6).
  • 10. 10 A pharmaceutical composition comprising the drug according to item 8 or 9, and a pharmacologically and pharmaceutically acceptable carrier.
  • FIG. 2 is a basic diagram when a compound of the present invention is synthesized using an existing RXR agonist as a lead compound.
  • 1 is a diagram illustrating a synthesis scheme of a target compound 12.
  • FIG. Example 1 1 is a diagram illustrating a synthesis scheme of a compound of target compound 18.
  • FIG. (Example 2) is a diagram illustrating a synthesis scheme of a compound of target compound 24.
  • (Example 3) 1 is a diagram illustrating a synthesis scheme of a compound of target compound 29.
  • FIG. 1 is a diagram illustrating a synthesis scheme of a target compound 12.
  • Example 2 It is a figure which shows the effect with respect to RXR-LXR and RXR-PPAR.
  • Example 3) It is a figure which shows the effect with respect to RXR-LXR and RXR-PPAR.
  • Example 3 It is a figure which shows blood transferability.
  • Example 4) It is a figure which shows the influence which acts on the blood triglyceride density
  • Example 5 It is a figure which shows a carrageenin edema test result.
  • Example 6) It is a figure which shows the result regarding a body weight increase and a liver weight.
  • Example 7) It is a figure which shows each agonist activity evaluation result of RXR (alpha), PPAR (gamma), LXR (alpha), and LXR (beta).
  • Example 8 It is a figure which shows each agonist activity evaluation result of RXR (alpha), PPAR (gamma), LXR (alpha), and LXR (beta).
  • the compound of the present invention is an RXR partial agonist compound and is represented by the following general formula I.
  • Formula I (Wherein R 1 is selected from the group consisting of iPr, iBu, (CH 2 ) n R 3.
  • R 2 is selected from OMe, O-iPr, O-iBu, iPr.
  • R 3 is OMe, (Selected from Me, Ph, COPh, and n is an integer from 1 to 5.)
  • R 3 when R 3 is Me in the general formula I, n is 5, and when R 1 is iPr or iBu, R 2 is selected from OMe, O-iPr, and O-iBu.
  • the compound of the present invention is a retinoid X receptor partial agonist compound of the general formula I, wherein R 1 is iPr or iBu and R 2 is OMe, O-iPr or O-iBu, or , R 1 is (CH 2 ) n R 3 , R 2 is iPr, R 3 is OMe, Me, Ph, or COPh, and n is an integer from 1 to 5, It is a body partial agonist compound.
  • the compound of the present invention is represented by the general formula II.
  • the compound of the present invention is a retinoid X receptor partial agonist compound: (A) a compound in which R 1 is iPr and R 2 is O-iPr in general formula I; (B) a compound of the general formula I, wherein R 1 is iBu and R 2 is O-iBu; (C) In the general formula I, a compound in which R 1 is iPr and R 2 is OMe, (D) a compound of the general formula I, wherein R 1 is (CH 2 ) n R 3 , R 2 is iPr, R 3 is Ph, and n is 3.
  • (E) a compound of the general formula I, wherein R 1 is (CH 2 ) n R 3 , R 2 is iPr, R 3 is COPh, and n is 1.
  • R 1 is (CH 2 ) n R 3 , R 2 is iPr, R 3 is Me, and n is 5, or
  • R 1 is (CH 2 ) n R 3 , R 2 is iPr, R 3 is OMe and n is 3.
  • RXR partial agonist compound of the present invention attention was focused on synthesizing a compound capable of improving the increase in blood TG, which was a common problem with existing RXR agonists.
  • Most RXR ligands are composed of a fat-soluble moiety consisting of a tetramethyltetrahydronaphthyl ring, an acidic moiety having a carboxylic acid, and a linker moiety that connects the two. It was expected that the fat-soluble high contribution of the tetramethyltetrahydronaphthyl ring, which is a fat-soluble structure, the RXR partial agonist of the present invention was converted by converting the fat-soluble site to a structure having a polar group.
  • Patent Document 1 Non-Patent Document 11, FIG. 1 (3)
  • Patent Document 2 a low fat-soluble RXR ⁇ selective agonist NEt-3IP
  • the RXR partial agonist compound of the present invention can be synthesized according to the synthesis procedure of the examples. Any compounds included in the scope of the present invention can be produced by appropriately modifying or altering the starting materials and reagents used in the methods shown in the Examples and the reaction conditions.
  • the RXR partial agonist compound of the present invention may be a pharmaceutically acceptable salt.
  • the present invention when there are isomers (for example, optical isomers, geometrical isomers and compatible isomers), the present invention includes those isomers, and also includes solvates, hydration And crystals of various shapes.
  • the pharmaceutically acceptable salt includes general pharmacologically and pharmaceutically acceptable salts.
  • specific examples of such salts are as follows.
  • Examples of basic addition salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; trimethylamine salts and triethylamine salts; dicyclohexylamine salts and ethanolamines.
  • Aliphatic amine salts such as salts, diethanolamine salts, triethanolamine salts and brocaine salts; aralkylamine salts such as N, N-dibenzylethylenediamine; and heterocyclic aromatics such as pyridine salts, picoline salts, quinoline salts and isoquinoline salts
  • tetramethylammonium salt tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, Quaternary ammonium salts such as tiger butyl ammonium salt; arginine; basic amino acid salts such as lysine salts.
  • the acid addition salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; for example, acetate, propionate, lactate, maleate , Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate; sulfonic acids such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate Salts; for example, acidic amino acids such as aspartate and glutamate.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate
  • Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate
  • sulfonic acids such as methanesulfonate, isethionate, benzenesulfonate
  • the compound of the present invention is a compound having a partial agonist activity with respect to RXR among the compounds represented by the general formula I or II.
  • Specific examples include compounds represented by Formula III.
  • the RXR partial agonist compound refers to a compound that exhibits agonist activity with respect to the RXR receptor but has a weaker action than a complete agonist. It is considered that the formation of a bond does not sufficiently activate the receptor, or a bond that exhibits agonist activity and antagonist activity is caused by different functional groups.
  • Such a compound binds at the site of action of the receptor and also has an antagonist activity that inhibits the binding of in vivo substances.
  • partial agonists may act as agonists or antagonists for various receptor subtypes of the same in vivo substance.
  • the partial agonist shown in the present invention can be expected to have selectivity for a coupled transcription factor required during gene transcription.
  • the RXR partial agonist compound of the present invention refers to a compound having an activity of 80% or less, more preferably 70% when the activity of LGD1069 (FIG. 1 (2)) known as a full agonist is 100%.
  • RXR is known as RXR ⁇ , RXR ⁇ , RXR ⁇ , and the RXR partial agonist compound of the present invention may be any compound having low RXR agonist activity, but preferably all RXR agonist activities are 80% or less. It refers to a compound, more preferably 70% or less.
  • the RXR partial agonist compound of the present invention is a compound having a preferable action such as a necessary anti-inflammatory action even though it exhibits only a partial agonist activity.
  • the RXR partial agonist compound of the present invention is characterized in that it is a compound that can promote lipid metabolism and improve the increase in blood TG as compared with known RXR full agonist compounds.
  • the compound of the present invention can also be referred to as a transcriptional regulatory compound.
  • the term “modulating action” or an analog thereof should be interpreted in the broadest sense including the enhancement or suppression of action. Whether the compound of the present invention has an enhancing action or an inhibiting action can be easily assayed according to the method specifically shown in the experimental examples of the present specification.
  • the above compound is a substance that expresses physiological activity by binding to a receptor that forms a heterodimer with RXR belonging to the nuclear receptor / superfamily existing in the nucleus of the cell, for example, active vitamin A metabolism It is possible to enhance or suppress the action of a retinoid compound including a product (All-trans® Retinoic® Acid: ATRA), a vitamin D compound such as eicosanoids, vitamin D3, or thyroxine or an orphan receptor ligand of unknown ligand.
  • a retinoid compound including a product (All-trans® Retinoic® Acid: ATRA), a vitamin D compound such as eicosanoids, vitamin D3, or thyroxine or an orphan receptor ligand of unknown ligand.
  • RXR agonistic or inhibitory compounds can be used to regulate the action of these physiologically active substances, and biological actions involving one or more nuclear receptors belonging to the nuclear receptors / superfamily. It can be used for the prevention and / or treatment of diseases involving abnormalities.
  • reagents and pharmaceutical agents containing the compound of the present invention as an active ingredient are included within the scope of the present invention.
  • a pharmaceutical it can be used, for example, as an anti-inflammatory agent or lipid metabolism regulator.
  • the dosage is not particularly limited.
  • a compound containing a retinoid such as retinoic acid as an active ingredient and the compound of the present invention in combination, or without using a medicine containing a retinoid, retinoic acid already present in the living body
  • Appropriate doses can be easily selected for all administration methods, such as when administering the drug of the present invention for the purpose of regulating the action of the drug.
  • the active ingredient can be used in the range of about 0.01 to 1000 mg per adult day.
  • the drug of the present invention can be administered either during the retinoid administration period and / or before or after that period. is there.
  • the RXR partial agonist compound of the present invention that is, one or more substances selected from any one of the compounds represented by formulas I to III may be administered as it is, but preferably the above-mentioned It is preferable to administer as an oral or parenteral pharmaceutical composition containing one or more substances.
  • Oral or parenteral pharmaceutical compositions can be prepared using pharmaceutical additives available to those skilled in the art, that is, pharmacologically and pharmaceutically acceptable carriers.
  • one or more of the above substances may be blended in a medicine containing a retinoid such as retinoic acid as an active ingredient, and used as a pharmaceutical composition in the form of a so-called mixture.
  • Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups.
  • the pharmaceutical composition suitable for parenteral administration includes for example, injections, drops, suppositories, inhalants, eye drops, nasal drops, ointments, creams, patches and the like can be mentioned.
  • Examples of pharmacologically and pharmaceutically acceptable carriers used in the production of the above pharmaceutical composition include, for example, excipients, disintegrating agents or disintegrating aids, binders, lubricants, coating agents, dyes, Diluents, bases, solubilizers or solubilizers, isotonic agents, pH adjusters, stabilizers, propellants, adhesives, and the like can be mentioned.
  • Example 1 Synthesis of the target compound 12a-o
  • the compound was synthesized according to the following synthesis scheme.
  • FIG. 3 shows the synthesis of compound 12 obtained by converting the 3-isopropoxy group of NEt-3IP (FIG. 1 (3)) into various alkoxy groups.
  • Intermediate 9 synthesized according to Non-Patent Document 11 was deisopropylated in methylene chloride by stirring at room temperature in the presence of aluminum trichloride, and then heated and stirred in DMF using various alkyl halides in the presence of K 2 CO 3 and KI. Thus, alkylation was performed. Further, the alkali-conditioned ester group was hydrolyzed to obtain the target compound 12a-o.
  • FIG. 4 shows the synthesis of a compound obtained by variously converting the 4-isopropyl group, that is, the synthesis method of target compound 18a-b.
  • 4-Nitrocatechol (13) is used as a starting material, and after dialkylation in DMF in the presence of K 2 CO 3 and KI, the nitro group is reduced to an amino group, and immediately 6-chloronicitic acid (6 -chloronicitinic acid) and an acid-catalyzed coupling reaction and methyl esterification gave Intermediate 16. This was N-ethylated and hydrolyzed under alkaline conditions to obtain the target compound 18a-b.
  • Example 3 Synthesis of Target Compound 24 A synthesis method of Compound 24 in which 4-isopropyl group is converted to methoxy group is shown in FIG. Using 5-Nitroguaiacol (19) as a starting material, the nitro group is converted to an amino group by catalytic reduction, and immediately, 6-chloronicitinic acid is coupled with an acid-catalyzed coupling reaction and methyl. Esterification was performed to obtain Intermediate 21. Isopropoxylation was performed in DMF in the presence of K 2 CO 3 and KI, followed by N-ethylation and hydrolysis under alkaline conditions to obtain the target compound 24.
  • a reporter gene assay was performed as a means of measuring transcriptional activity.
  • An RXR receptor protein expression plasmid and a reporter plasmid are introduced into COS-1 cells and overexpressed.
  • the RXR agonist binds to the receptor, transcription occurs in a ligand-dependent manner, and a luciferase, which is a reporter protein, is generated downstream thereof.
  • this fusion protein binds to the binding site on the reporter plasmid, its transcription begins and production of downstream luciferase begins.
  • RXR agonist activity was measured by measuring the luciferase activity.
  • DMEM Dulbecco's modified Eagle MEM medium
  • FBS fetal bovine serum
  • Passage is by removing the culture supernatant of cells cultured in a 10mm culture dish, collecting the cells by trypsin treatment, centrifuging at 4 ° C, 1000rpm, 3 minutes, adding growth medium to disperse the cells, 37 ° C, This was carried out in a 100 mm culture dish (growth medium 15 mL) in the presence of 5% CO 2 .
  • RXR agonist activities of RXR ⁇ , RXR ⁇ or RXR ⁇ are shown in Tables 1 and 2 below. a) All values showed values after 3 measurements. b) The EC 50 value indicates the concentration that gives half of the maximum transcriptional activation ability when COS-1 cells were allowed to act at 10 ⁇ 9 to 10 ⁇ 5 M. c) For the values of NEt-3IP, NEt-4IP and NEt-3IB, the values shown in Non-Patent Document 11 were referred to. d) E max (%) was calculated with the value obtained by applying 1 ⁇ M of LGD1069 (2) as 100%.
  • each RXR agonist activity of LGD1069 (2) and NEt-3ME (12n) is shown in FIG. This confirmed that NEt-3ME (12n) has partial agonist activity for each RXR.
  • NEt-3ME (12n) has RXR partial agonist activity, it is considered that when it coexists with RXR full agonist, it exhibits RXR antagonist activity that weakens the activity of the full agonist.
  • NEt-3ME (12n) was tested for competition with the existing RXR full agonist LGD1069 (2).
  • the RXR full agonist NEt-3NB (12k) structurally similar to NEt-3ME (12n) and the known RXR antagonist PA452 (33) were used.
  • NEt-3ME (12n) was confirmed to suppress the activity value of LGD1069 (2) (FIGS. 8 and 9).
  • NEt-3ME (12n) shows an activation rate of about 60% at 10 -5 M alone or in the presence of LGD1069 (2).
  • RXR full agonist NEt-3NB (12k) and RXR antagonist PA452 It was confirmed that the effect on RXR was clearly different from (33). This indicates that NEt-3ME (12n) maintains the moderate RXR activation ability necessary for the therapeutic effect and can be a regulator when RXR is excessively activated.
  • NEt-3ME (12n) hardly activated RXR ⁇ -LXR ⁇ , and did not activate RXR ⁇ -PPAR ⁇ and RXR ⁇ -PPAR ⁇ at all. Since LXR ⁇ is known to be involved in TG elevation, NEt-3ME (12n) is expected to reduce TG elevation in vivo. On the other hand, in activation against RXR ⁇ -LXR ⁇ , which is believed to contribute to anti-inflammatory action, NEt-3ME (12n) is compared to that of NEt-3IP (3), PA024 (34), NEt-TMN (35) However, the activation ability was comparable to 1 ⁇ M LXR pan agonist AA-09 or 1 ⁇ M PPAR agonist TIPP (FIGS. 10 and 11). Therefore, NEt-3ME (12n) was expected to exert an anti-inflammatory effect by activating RXR ⁇ -LXR ⁇ while avoiding TG elevation in vivo.
  • the blood concentration was measured using a sample prepared by the following experimental method. Fasted 5-week-old male ICR mice (8 per group) were orally administered at 30 mg / kg, and each mouse was euthanized under ether anesthesia every 1, 3, 6, 12 hours Blood was collected. The collected blood was centrifuged at 4 ° C. and 4,400 g, and 100 ⁇ L of the supernatant was collected. Add 100 ⁇ L of ice-cooled 5 mM aqueous ammonium acetate solution (adjusted to pH 5.0 with acetic acid), add 1 mL of ethyl acetate, stir with vortex (R) for 30 seconds, and add 800 ⁇ L of the supernatant. Was sorted.
  • the TG concentration was measured using a sample prepared by the following experimental method.
  • a fasted 5-week-old male ICR mouse (8 per group) was orally administered at 30 mg / kg. Every 1, 3, 6, 12 hours, individual mice were euthanized under ether anesthesia and then blood was collected. The collected blood was centrifuged at 4,400 g at 4 ° C, 50 ⁇ L of the supernatant was collected, added to a 96-well plate, and using a commercially available triglyceride measurement kit (Triglyceride Test TM Wako, Wako Pure Chemical Industries) It was measured by the absorbance method.
  • this compound showed a significant anti-inflammatory effect at 10 mg / kg.
  • the present compound showed no significant increase in body weight or liver weight when administered at 30 mg / kg, compared to the RXR full agonists NEt-3IP and NEt-TMN.
  • each agonist was expressed using cells in which PPAR or LXR receptor protein and reporter protein were expressed in COS-1 cells. Activity was confirmed by measuring luciferase activity. 1 ⁇ M LGD1069 for RXR, 1 ⁇ M TIPP703 (Bioorganic & Medicinal Chemistry Letters, 18, 2008, 4525-4528) for PPAR, 1 ⁇ M AA-09 for LXR (carba-T09017317 analog; Heterocyles, 78, 2009, 2209 The relative activity was calculated with the activation ability of -2216) as 100%.
  • NEt-3ME (12n) has partial agonist activity against RXR ⁇ , but hardly showed agonist activity against PPAR ⁇ , LXR ⁇ , and LXR ⁇ .
  • the RXR partial agonist compound of the present invention migrates well into the blood and disappears quickly in the blood concentration test at the time of oral administration. Moreover, when the value of blood TG in oral administration was measured, it was found that the effect of increasing TG was avoided. Furthermore, when the anti-inflammatory effect was evaluated by the mouse carrageenan edema test, a significant anti-inflammatory effect was observed. In this compound, cLogP value that is an index of fat solubility is 4.7 (NEt-3ME), which has succeeded in drastically reducing fat solubility compared to known RXR partial agonists, and Lipinski's unsuitable for oral administration It is an attractive compound that avoids Rule of Five.
  • the compound of the present invention alleviates the problem that a full agonist may cause homeostasis failure due to excessive receptor activity, and is excellent in spite of suppressing blood TG, which has been regarded as a conventional problem. Since it showed an anti-inflammatory effect, it is considered to have an effective action with few side effects in pharmaceutical use. It can be used as an anti-inflammatory agent or lipid metabolism improving agent comprising the RXR partial agonist compound of the present invention as an active ingredient.

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  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention porte sur un nouveau composé réxinoïde qui a une liposolubilité réduite et une innocuité améliorée. Il est supposé qu'un noyau tétraméthyltétrahydronaphtyle, qui est une structure liposoluble, contribuerait à la liposolubilité élevée d'un ligand des RXR. Selon cette hypothèse, un agoniste partiel des RXR, qui a une liposolubilité réduite et qui peut présenter un excellent effet pharmacologique, est synthétisé avec succès par conversion du site liposoluble en une structure comportant un groupe polaire. Dans la synthèse du composé susmentionné, un agoniste sélectif des RXRαβ faiblement liposoluble, NEt-31P, comportant un groupe alcoxy est utilisé comme composé tête de série.
PCT/JP2010/001317 2009-02-27 2010-02-26 Composé agoniste partiel des récepteurs des rétinoïdes x Ceased WO2010098125A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017002874A1 (fr) * 2015-06-30 2017-01-05 国立大学法人 岡山大学 Médicament pour la prévention ou le traitement d'une maladie inflammatoire de l'intestin
CN107708696A (zh) * 2015-06-30 2018-02-16 国立大学法人冈山大学 炎症性肠病的预防或治疗用药剂
JPWO2017002874A1 (ja) * 2015-06-30 2018-04-19 国立大学法人 岡山大学 炎症性腸疾患の予防又は治療用薬剤
CN107708696B (zh) * 2015-06-30 2021-05-28 国立大学法人冈山大学 炎症性肠病的预防或治疗用药剂
US11103489B2 (en) 2015-06-30 2021-08-31 National University Corporation Okayama University Drug for preventing or treating inflammatory bowel disease

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