WO2003005025A1 - Procedes d'identification de composes modulant l'activite du ppar-gamma - Google Patents

Procedes d'identification de composes modulant l'activite du ppar-gamma Download PDF

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Publication number
WO2003005025A1
WO2003005025A1 PCT/SE2002/001322 SE0201322W WO03005025A1 WO 2003005025 A1 WO2003005025 A1 WO 2003005025A1 SE 0201322 W SE0201322 W SE 0201322W WO 03005025 A1 WO03005025 A1 WO 03005025A1
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Prior art keywords
atom
leu
pparγ
lys
compound
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PCT/SE2002/001322
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English (en)
Inventor
Anna-Lena Gustavsson
Stefan Svensson
Jonas Uppenberg
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Biovitrum Ab
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Priority claimed from SE0102384A external-priority patent/SE0102384D0/xx
Application filed by Biovitrum Ab filed Critical Biovitrum Ab
Publication of WO2003005025A1 publication Critical patent/WO2003005025A1/fr

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    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • C—CHEMISTRY; METALLURGY
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    • C07K—PEPTIDES
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • the present invention relates to compounds modulating PPAR ⁇ by a previously unknown binding mode.
  • Co-crystal structures of PPAR ⁇ and ligands to PPAR ⁇ have been determined by X-ray diffraction.
  • the identified binding mode of the compounds reveals a novel pharmacophoric pattern for PPAR ⁇ ligands with the potential to selectively modulate the binding of coactivators and activate gene transcription.
  • the invention comprises the use of this pharmacophore model and the X-ray structure as design tools for new classes of PPAR ⁇ modulators. These classes of modulators are predicted to be useful in the treatment of metabolic diseases, e.g. type II diabetes.
  • test compounds for binding to the PPAR ⁇ ligand binding domain; and (ii) identifying a test compound that selectively modulates the activity of PPAR ⁇ ; wherein said compound comprises:
  • R can be independently substituted in one or more positions with methyl, ethyl, isopropyl, methoxy, thiomethoxy ethoxy, methylsulfonyl, formyl, acetyl, nitro, cyano, methylhydroxy, methylamino, carboxy, trifluoromethyl, trifluoromethoxy, chloro, fluoro, bromo, iodo, benzylox , amino, dimethylamino, acetylamino, phenyl, phenoxy, or benzoyl.
  • Examples of said C g alkoxy include methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy.
  • halogen shall mean fluorine, chlorine, bromine or iodine.
  • heteroaryl denotes a mono- or bicyclic ring system (only one ring need to be aromatic, and substitution may be in any ring) having from 5 to 10 ring atoms (which are carbon atoms), in which one or more of the carbon ring atoms are other than carbon, such as nitrogen, oxygen and sulfur.
  • One embodiment is the crystal of described above, wherein the PPAR ⁇ comprises an amino acid sequence containing amino acids amino acids Gly284,
  • This invention also features a method of using the protein-ligand crystals described herein for identifying a compound that binds to a PPAR ⁇ ligand binding domain.
  • the method includes the steps of:
  • the computer may comprise a central processing unit, a working memory, for example, random access memory and/or storage memory in the form of one or more disk drives (e.g., floppy, ZipTM, jazzTM), tape drives, CD-ROM drives, DVD drives, and the like, a display terminal such as for example, a cathode ray tube type or a liquid crystal type display, and input and output lines for data transmission, including a keyboard and/or mouse controller.
  • the computer may be a stand-alone, or connected to a network and/or shared server.
  • Data storage materials include, for example, hard drives, floppy, ZipTM and JazzTM type disks, tapes, CDs, and DVDs.
  • the invention relates to a computer readable data storage material encoded with computer readable data comprising structure coordinates according to Table III]
  • PPAR ⁇ -ligand e.g., lithium 2-[(2,4- dichlorobenzoyl)amino]-5-(thienylmethoxy]benzoate
  • PPAR ⁇ -ligand e.g., lithium 2-[(2,4- dichlorobenzoyl)amino]-5-(thienylmethoxy]benzoate
  • GRID available form Oxford University, UK
  • MCSS available from Molecular Simulations Inc., Burlington, MA
  • AUTODOCK available from Oxford Molecular Group
  • FLEX X available from Tripos, St. Louis. MO
  • DOCK available from University of California, San Francisco
  • CAVEAT available from University of California, Berkeley
  • HOOK available from Molecular Simulations Inc., Burlington, MA
  • 3D database systems such as MACCS-3D (available from MDL Information Systems, San Leandro, CA), UNITY (available from Tripos, St. Louis.
  • “An effective amount” refers to an amount of a compound which confers a therapeutic effect on the treated subject (eg., a human, a mammal, a horse, a dog, or a cat).
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • the dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy.
  • the compounds can be prepared by, or in analogy with, standard synthetic methods, and especially according to, or in analogy with, the methods described in the co-pending international patent application derived from Swedish patent application No. 0102384- 5, filed July 3, 2001.
  • the compounds described above can be prepared by, or in analogy with, standard synthetic methods, and especially according to, or in analogy with, the following methods.
  • the chemicals used in the above-described synthetic routes may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents.
  • the methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds of Formula (I).
  • various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M.
  • TMAD 183 mg, 1.06 mmol
  • TMAD 183 mg, 1.06 mmol
  • a suspension of methyl 2- [(2,4- dichlorobenzoyl)amino]-5-hydroxybenzoate 240 mg, 0.71 mmol; prepared in Example XX
  • polymer bound triphenylphosphine 480 mg, 1.4 mmol
  • thiophene-2-methanol 73 ⁇ l, 0.78 mmol
  • the suspension was shaken at room temperature over night and filtered through a plug of Celite.
  • the cells are treated with trypsin, transferred to 96-well microplates and allowed to settle. Induction is performed for 24 hours by applying different concentrations of compounds diluted in DMSO or DMSO alone (vehicle). Subsequently, the cells are lysed and luciferase activity measured, according to standard procedures.
  • the compounds of Formula I exhibit EC50 values on PPAR ⁇ in the range of 0.3 to 50 ⁇ M.
  • ATOM 2 C ALA A 200 2.711 5, .546 37. .067 1. .00 90. .10 A
  • ATOM 36 CA LEU A 204 10.123 -1, .532 35. .081 1. .00 44. .17 A
  • ATOM 119 CA ALA A 215 17 .965 5, .216 23, .529 1. .00 28, .93 A
  • ATOM 120 CB ALA A 215 17, .712 5, .433 25, .023 1. .00 24, .68 A
  • ATOM 121 C ALA A 215 19, .474 5, .133 23, .259 1. .00 29. .08 A
  • ATOM 140 C HIS A 217 21, .181 4, .688 18, .870 1. .00 31, .05 A
  • ATOM 151 CA TYR A 219 22. .837 8, .123 21, .088 1. .00 24, .74 A
  • ATOM 177 CA TYR A 222 24. .105 10, .889 17. .416 1. .00 23. .74 A
  • ATOM 180 CDl TYR A 222 22. .519 13. .609 18. .909 1. .00 11. .23 A
  • ATOM 194 C ILE A 223 28. .552 10, .713 17. .334 1. .00 37. .76 A
  • ATOM 206 CA SER A 225 26. .405 12, .127 13. .126 1. .00 25, .92 A
  • ATOM 356 CA SER A 245 41 .501 27 .227 23 .845 1, .00 71, .46 A
  • ATOM 400 CD2 TYR A 250 37, .774 40, .749 22, .278 1. .00 37, .30 A
  • ATOM 404 C TYR A 250 34 .678 42, .298 19, .905 1. .00 34 .36 A
  • ATOM 406 N ASP A 251 35, .729 42, .710 19, .208 1. .00 35 .33 A
  • ATOM 414 N MET A 252 35, .900 44, .787 16, .169 1. .00 43, .95 A
  • ATOM 415 CA MET A 252 36, .371 44. .807 14, .797 1. .00 47, .31 A
  • ATOM 416 CB MET A 252 36, .119 46. .186 14. .163 1. .00 51, .27 A
  • ATOM 420 C MET A 252 37, .852 44, .451 14, .764 1. .00 46 .82 A
  • ATOM 424 CB ASN A 253 40, .800 45, .345 16, .823 1. .00 46 .46 A
  • ATOM 428 C ASN A 253 40 .247 43, .032 16 .067 1, .00 40 .00 A
  • ATOM 457 CE MET A 257 45, .946 41, .373 16, .786 1. .00 77. .57 A
  • ATOM 458 C MET A 257 42, .676 37, .555 14, .766 1. .00 65. .79 A
  • ATOM 479 C ASP A 260 44, .348 33, .578 11, .575 1. .00 88. .09 A
  • ATOM 506 CA LYS B 275 33 .519 41 .716 2 .089 1 .00 89 .92 B
  • ATOM 536 CA ILE B 279 28. .069 39. .926 5. .651 1. .00 26. .12 B
  • ATOM 544 CA ARG B 280 31. ,323 37. ,954 5. .796 1. 00 33. ,45 B
  • ATOM 624 CA SER B 289 24. .048 25, .668 8, .529 1. .00 16, .84 B
  • ATOM 637 CA GLU B 291 26. .540 21, .423 6, .692 1. .00 19, .54 B
  • ATOM 640 CD GLU B 291 30. .305 21, .256 7. .594 1. .00 43, .75 B
  • ATOM 646 CA ALA B 292 24. .288 20. .951 9. .693 1. .00 16, .19 B
  • ATOM 658 CA GLN B 294 23. .503 17, .386 5. .883 1. .00 12, .39 B
  • ATOM 700 CA TYR B 299 21, .147 11, .221 11. .612 1. .00 19, .04 B
  • ATOM 712 CA ALA B 300 17. .531 10. .986 10. ,530 1. ,00 16. .85 B
  • ATOM 714 C ALA B 300 17. .353 9. .607 9. ,935 1. .00 13. .77 B
  • ATOM 736 CDl ILE B 762 15, .200 10, .414 13, .828 1. .00 6. .15 B
  • ATOM 737 C ILE B 762 15, .183 5, .474 12, .942 1. .00 17. .74 B
  • ATOM 741 CA PRO B 304 14, .467 3, .166 13, .449 1. .00 15, .38 B
  • ATOM 770 CB ASN B 308 10, .163 2. .080 6, .280 1. .00 39, .07 B
  • ATOM 778 CB LEU B 309 8. .322 7. .547 6. .617 1. .00 19. .27 B
  • ATOM 802 CB ASN B 312 6, .061 12. .115 -0, .672 1. .00 36. .61 B
  • ATOM 806 C ASN B 312 7, .419 12. .912 1, .261 1. .00 24. .96 B
  • ATOM 814 C ASP B 313 8 .187 12, .856 4 .429 1. .00 15, .53 B
  • ATOM 820 CD GLN B 314 12, .307 9, .055 3, .901 1. .00 26, .57 B
  • ATOM 826 CA VAL B 315 11. .316 15. .487 2, .779 1. .00 11. .68 B
  • ATOM 833 CA THR B 316 8. .617 17. .372 4. .687 1. 00 11. .97 B
  • ATOM 840 CA LEU B 317 9 .737 16, .181 8 .067 1, .00 8 .53 B
  • ATOM 848 CA LEU B 318 13 .178 17, .572 7 .255 1. .00 16, .34 B

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Abstract

L'invention porte sur un procédé d'identification de composés pouvant de fixer au domaine de fixation des ligands du récepteur gamma activé par le proliférateur de péroxisome (PPARη), et modulant sélectivement l'activité du PPARη. Ledit procédé consiste à trouver des composés adaptés spatialement et préférentiellement domaine de fixation du PPARη. lesdits composés comprennent: a) un groupe benzoate interagissant avec des parties des Ile341, Cys285 et Gly284, b) un groupe carboxylate interagissant avec des parties des Ser342, et c) un groupe aromatique interagissant avec des parties des Leu330, Ile326, Arg288, Leu333 et Met329 du PPAR-gamma. L'invention porte également sur des préparations pharmaceutiques traitant ou prévenant le diabète, et sur un moyen de stockage lisible par ordinateur.
PCT/SE2002/001322 2001-07-03 2002-07-03 Procedes d'identification de composes modulant l'activite du ppar-gamma WO2003005025A1 (fr)

Applications Claiming Priority (4)

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SE0102384-5 2001-07-03
SE0102384A SE0102384D0 (sv) 2001-07-03 2001-07-03 New compounds
US30470601P 2001-07-11 2001-07-11
US60/304,706 2001-07-11

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