Design, synthesis, and structure-activity relationship studies of novel 2,4,6-trisubstituted-5-pyrimidinecarboxylic acids as peroxisome proliferator-activated receptor γ (PPARγ) partial agonists with comparable antidiabetic efficacy to rosiglitazone

Journal of Medicinal Chemistry

Volumn 53, Issue 13, 2010, Pages 5012-5024

  Seto, Shigeki ^a   Okada, Kyoko ^a   Kiyota, Koichi ^a   Isogai, Shigeki ^a   Iwago, Maki ^a   Shinozaki, Takehiro ^a   Kitamura, Yoshiaki ^a   Kohno, Yasushi ^a   Murakami, Koji ^a  

^a KYORIN PHARMACEUTICAL CO LTD   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

2 (BUTYLTHIO) 4,6 DICHLORO PYRIMIDINE; 2 (BUTYLTHIO) 4,6 DICHLOROPYRIMIDINE 5 CARBOXYLIC ACID; 4 (BENZYLAMINO) 6 (BENZYLTHIO) 2 (METHYLTHIO)PYRIMIDINE 5 CARBOXYLIC ACID; 4 (BENZYLTHIO) 2 (METHYLTHIO) 6 (2 PHENETHYLAMINO)PYRIMIDINE 5 CARBOXYLIC ACID; 4 (BENZYLTHIO) 2 (METHYLTHIO) 6 (2 PYRIDYLMETHYLAMINO)PYRIMIDINE 5 CARBOXYLIC ACID; 4 (BENZYLTHIO) 2 (METHYLTHIO) 6 (3 PYRIDYLMETHYLAMINO)PYRIMIDINE 5 CARBOXYLIC ACID; 4 ANILINO 6 (BENZYLTHIO) 2 (METHYLTHIO)PYRIMIDINE 5 CARBOXYLIC ACID; 4,6 BISBENZYLTHIO 2 METHYLTHIOPYRIMIDINE 5 CARBOXYLIC ACID; 4,6 DICHLORO 2 (OCTYLTHIO)PYRIMIDINE; 4,6 DICHLOROPYRIMIDINE 5 CARBOXYLIC ACID; ANTIDIABETIC AGENT; BALOGLITAZONE; CARBOXYLIC ACID DERIVATIVE; FK 614; L 764406; METAGLIDASEN; METHYL 2 (BUTYLTHIO) 4,6 DICHLOROPYRIMIDINE 5 CARBOXYLIC ACID; METHYL 4 (BENZYLAMINO) 6 CHLORO 2 (HEPTYLAMINO)PYRIMIDINE 5 CARBOXYLIC ACID; METHYL 4 (BENZYLTHIO) 2 (BUTYLTHIO) 6 CHLOROPYRIMIDINE 5 CARBOXYLIC ACID; METHYL 4 (BENZYLTHIO) 6 CHLORO 2 (METHYLTHIO)PYRIMIDINE 5 CARBOXYLIC ACID; METHYL 4 (BENZYLTHIO) 6 CHLORO 2 (OCTYLTHIO)PYRIMIDINE 5 CARBOXYLIC ACID; METHYL 4 (BENZYLTHIO) 6 CHLOROPYRIMIDINE 5 CARBOXYLIC ACID; METHYL 4,6 DICHLORO 2 (OCTYLTHIO)PYRIMIDINE 5 CARBOXYLIC ACID; METHYL 4,6 DICHLOROPYRIMIDINE 5 CARBOXYLIC ACID; MK 0533; PARTIAL AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PYRIMIDINE DERIVATIVE; ROSIGLITAZONE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ADIPOCYTE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CELL DIFFERENTIATION; CELL STRAIN 3T3; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG EFFICACY; DRUG SYNTHESIS; EMBRYO; HUMAN; HYDROGEN BOND; MOUSE; NONHUMAN; PHARMACOPHORE; RAT; SCREENING; STRUCTURE ACTIVITY RELATION;

3T3-L1 CELLS; ANIMALS; CARBOXYLIC ACIDS; CRYSTALLOGRAPHY, X-RAY; DIABETES MELLITUS, TYPE 2; HYPOGLYCEMIC AGENTS; MAGNETIC RESONANCE SPECTROSCOPY; MALE; MASS SPECTROMETRY; MICE; PPAR GAMMA; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLIDINEDIONES;

EID: 77954328462     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm100443s     Document Type: Article

References (45)

1. Milions, H. J.; Elisaf, M. S.; Mikhailidis, D. P. Treatment of dyslipidaemias in patients with established vascular disease: a revival of the fibrates Curr. Med. Res. Opin. 2000, 16, 21-32
2. Schoonjans, K.; Staels, B.; Auwerx, J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibtrates and fatty acid on gene expression J. Lipid. Res. 1996, 37, 907-925
3. Staels, B.; Auwerx, J. Role of PPAR in the pharmacological regulation of lipoprotein metabolism by fibrates and thiazolidinediones Curr. Pharm. Des. 1997, 3, 1-14 (Pubitemid 27215884)
4. Murakami, K.; Tobe, K.; Ide, T.; Ohashi, M.; Akunuma, Y.; Yazaki, Y.; Kadowaki, T. A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-α) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats Diabetes 1998, 47, 1841-1847
5. Momose, Y.; Meguro, K.; Ikeda, H.; Hatanaka, C.; Oi, S.; Sodha, T. Studies on antidiabetic agents. X. Synthesis and biological activities of pioglitazone and related compounds Chem. Pharm. Bull. 1991, 39, 1440-1445
6. Cantello, B. C.; Cawthorne, M. A.; Haigh, D.; Hindley, R. M.; Smith, S. A.; Thurlby, P. [[ω-(Heterocycliylamino)alkoxy]benzyl]-2,4- thiazolidinesdiones as potent antidiabetic agents J. Med. Chem. 1994, 37, 3977-3985
7. Hamefeld, M.; Belcher, G. Safety profile of pioglitazone Int. J. Clin. Pract. 2001, 27-31
8. Sorbera, L. A.; Rabbasseda, X.; Castaner, J. Rosiglitazone malonate (BRL-49653C; Avantia): antidiabetic; insulin sensitizer Drugs Future 1998, 23, 977-985
9. Berger, J. P.; Petro, A. E.; MacNaul, K. L.; Kelly, L. J.; Zhang, B. B.; Richards, K.; Elbrecht, A.; Johnson, B. A.; Zhou, G.; Doebber, T. W.; Biswas, C.; Parikh, M.; Sharma, N.; Tanen, M. R.; Thompson, G. M.; Ventre, J.; Adams, A. D.; Mosely, R.; Surwit, R. S.; Moller, D. E. Distinct properties and advantages of a novel peroxisome proliferator-activated protein γ selective modulator Mol. Endocrinol. 2003, 17, 662-676
10. Acton, J, J.; Black, R. M.; Jones, A. B.; Moller, D. E.; Colwell, L.; Doebber, T. W.; MacNaul, K. L.; Berger, J.; Wood, H. B. Benzoyl 2-methyl indoles as selective PPARγ modulators Bioorg. Med. Chem. Lett. 2005, 15, 357-362
11. Berger, J. P.; Akiyama, T. E.; Meinke, P. T. PPARs: therapeutic targets for metabolic disease Trends Pharmacol. Sci. 2005, 26, 244-251
12. Dropinski, J. F.; Akiyama, T.; Einstein, M.; Habulihaz, B.; Doebber, T.; Berger, J. P.; Meinke, P. T.; Shi, G. Q. Synthesis and biological activities of novel aryl indole-2-carboxylic acid analogues as PPARγ partial agonists Bioorg. Med. Chem. Lett. 2005, 15, 5035-5038
13. Cock, T. A.; Houten, S. M.; Auwerx, J. Peroxisome proliferator-activated receptor γ: too much of a good thing cause harm EMBO J. 2004, 5, 142-147
14. Larsen, P. J.; Kykkegaard, K.; Larsen, L. K.; Fleckner, J.; Sauerberg, P.; Wassermann, K.; Wulff, E. M. Dissosiation of antihyperglycemic and adverse effects of partial peroxisome proliferator-activated receptor (PPARγ) agonist balaglitazone Eur. J. Phermacol. 2008, 596, 173-179
15. Minoura, H.; Takeshita, S.; Ita, M.; Hirosumi, J.; Mabuchi, M.; Kawamura, I.; Nakajima, S.; Nakayama, O.; Kayakiri, H.; Oku, T.; Ohkubo-Suzuki, A.; Fukagawa, M.; Kojo, H.; Hanioka, K.; Yamasaki, N.; Imoto, T.; Kobayashi, Y.; Mutoh, S. Pharmacological characteristics of a novel nonthiazolidinedione insulin sensitizer, FK-614 Eur. J. Pharmacol. 2004, 494, 273-281
16. Acton, J. J., III; Akiyama, T. E.; Chang, C. H.; Colwell, L.; Debenham, S.; Doebber, T.; Einstein, M.; Liu, K.; McCann, M. E.; Moller, D. E.; Muise, E. S.; Tan, Y.; Thompson, J. R.; Wong, K. K.; Wu, M.; Xu, L.; Meinke, P. T.; Berger, J. P.; Wood, H. B. Discovery of (2 R)-2-(3-{3-[(4-methoxyphenyl) carbonyl]-2-methyl-6-(trifluoromethoxy)-1 H -indol-1-yl}phenoxy)butanoic acid (MK-0533): a novel selective peroxisome proliferator-activated receptor γ modulator for the treatment of type 2 diabetes mellitus with a reduced potential to increase plasma and extracellular fluid volume J. Med. Chem. 2009, 52 (13) 3846-3854
17. Gregoire, F. M.; Zhang, F.; Clarke, H. J.; Gustafson, T. A.; Sears, D. D.; Favelyukis, S.; Lenhard, J.; Rentzeperis, D.; Clemens, L. E.; Mu, Y.; Lavan, B. E. MBX-102/JNJ39659100, a novel peroxisome proliferator-activated receptor-ligand with weak transactivation activity retains antidiabetic properties in the absence of weight gain and edema Mol. Endocrinol. 2009, 23, 975-988
18. Shimaya, A.; Kurosaki, E.; Nakano, R.; Hirayama, R.; Shibasaki, M.; Shikama, H. The novel hypoglycemic agent YM440 normalizes hyperglycemia without changing body fat weight in diabetic db/db mice Metabolism 2000, 49, 411-417
19. Rubenstrunk, A.; Hanf, R.; Hum, D. W.; Fruchart, J. C.; Staels, B. Safety issues and prospects for the future generation of PPAR modulators Biochim. Biophys. Acta 2007, 1771, 1065-1081
20. Bruning, J. B.; Chalmers, M. J.; Prasad, S.; Busby, S. A.; Kamenecka, T. M.; He, Y.; Nettles, K. W.; Griffin, P. R. Partial agonists activate PPARγ using a helix 12 independent mechanism Structure 2007, 15, 1258-1271
21. Elbrecht, A.; Chen, Y.; Adams, A.; Berger, J.; Griffin, P.; Klatt, T.; Zhang, B.; Menke, J.; Zhou, G.; Smith, R. G.; Moller, D. E. L-764406 is a partial agonist of human peroxisome proliferator-activated receptor γ J. Biol. Chem. 1999, 274, 7913-7922
22. Evans, D. C.; Watt, A. P.; Nicoll-Griffith, D. A.; Baillie, T. A. Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development Chem. Res. Toxicol. 2004, 17, 3-16
23. Seto, S.; Kohno, Y. Chemoselective displacement of methylsulfinyl group with amines to provide 2-(alkylamino)-4,6-(disubstituted)pyrimidine-5-carboxylic acid Heterocycles 2009, 78, 2263-2275
24. 6-Substituted 8-alkyl-2-phenylmethylsulfanyl-adenines. II J. Heterocycl. Chem. 2004, 41, 581-585
25. Bell, L.; McGuire, H. M.; Freeman, G. A. Chemistry of 5-pyrimidinecarboxaldehydes J. Heterocycl. Chem. 1983, 20, 41-44
26. Shimadzu, M.; Ishikawa, N.; Yamamoto, K.; Tanaka, A. Studies on furan derivatives. XIV [1]. Nucleophilic substitution of methyl 5-nitro-2- furancarboxylate and 5-nitrofuran-2-nitrile J. Heterocycl. Chem. 1986, 23, 1179-1182
27. 1 antagonists Bioorg. Med. Chem. 2005, 13, 5717-5732
28. Pochetti, G.; Godio, C.; Mitro, N.; Caruso, D.; Galmozzi, A.; Scurati, S.; Loiodice, F.; Fracchiolla, G.; Tortorella, P.; Laghezza, A.; Lavecchia, A.; Novellino, E.; Mazza, F.; Crestani, M. Insights into the mechanism of partial agonism J. Biol. Chem. 2007, 282, 17314-17324
29. Nolte, C.; Wisely, G. B.; Westin, S.; Cobb, J. E.; Lambert, M. H.; Kurokawa, R.; Rosenfield, M. G.; Willson, T. M.; Glass, C. K.; Milburn, M. V. Ligand binding and coactivator assembly of the peroxisome proliferator-activated receptor γ Nature (London) 1998, 395, 137-143
30. Oberfield, J. L.; Collins, J. L.; Holmes, C. P.; Goreham, D. M.; Cooper, J. P.; Cobb, J. E.; Lehmann, J. M.; Plunket, K.; Miller, A. B.; Milburn, M. V.; Kliewer, S. A.; Willson, T. M. A peroxysome proliferator-activated receptor γ ligand inhibits adipocyte differentiation Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 6102-6106
31. Burgermeister, E.; Schnoebelen, A.; Flament, A.; Benzs, J.; Stihle, M.; Gsell, B.; Rufer, A.; Ruf, A.; Kuhn, B.; Marki, H. P.; Mizrahi, J.; Sebokova, E.; Niesor, E.; Meyer, M. A novel partial agonist of peroxysome proliferator-activated receptor-γ (PPARγ) recruits PPARγ-coactivator-1a, prevents triglyceride accumulation, and potentiates insulin signaling in vitro Mol. Endocrinol. 2006, 20, 809-830
32. Einstein, M.; Akiyama, T. E.; Castriota, G. A.; Wang, C. F.; McKeever, B.; Mosley, R. T.; Becker, J. W.; Moller, D. E.; Meinke, P. T.; Wood, H. B.; Berger, J. P. The differential interactions of peroxysome proliferator-activated receptor γ ligands with Tyr473 is a physical basis for their unique biological activities Mol. Pharmacol. 2008, 73, 62-74
33. Tontonoz, P.; Hu, E.; Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor Cell 1994, 79, 1147-1156
34. Wu, Z.; Bucher, N. L.; Farmer, S. R. Induction of peroxisome proliferator-activated receptor γ during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPβ, C/EBPδ, and glucocorticoids Mol. Cell. Biol. 1996, 16, 4128-4136
35. Thompson, G. M.; Trainor, D.; Tanen, M.; Biswas, C.; LaCerte, C.; Berger, J. P.; Kelly, L. J. A high-capacity assay for PPARγ ligand regulation of endogenous aP2 expression in 3T3-L1 cells Anal. Biochem. 2004, 330, 21-28
36. Tugwood, J. D.; Montegue, C. T. Biology and toxicology of PPAR gamma ligands Hum. Exp. Toxicol. 2002, 21, 429-437
37. Liu, W.; Liu, K.; Wood, H. B.; McCann, M. E.; Doebber, T. W.; Chang, C. H.; Akiyama, T. E.; Einstein, M.; Berger, J. P.; Meinke, P. T. Discovery of a peroxisome proliferator activated receptor γ (PPARγ) modulator with balanced PPARα activity for the treatment of type 2 diabetes and dyslipidemia J. Med. Chem. 2009, 52, 4443-4453
38. Acton, J. J.; Black, R. M.; Jones, A. B.; Moller, D. E.; Cowell, L.; Doebber, T. W.; Macnaul, K. L.; Berger, J.; Wood, H. B. Benzoyl 2-methyl indoles as selective PPARγ modulators Bioorg. Med. Chem. Lett. 2005, 15, 357-362
39. Rocchi, S.; Picard, F.; Vamecq, J.; Gelman, L.; Potier, N.; Zeyer, D.; Dubuquoy, L.; Bac, P.; Champy, M.-F.; Plunket, K. D.; Leesnitzer, L. M.; Blanchard, S. G.; Desreumaux, P.; Moras, D.; Renaud, J.-P.; Auwerx, J. A unique PPARγ ligand with potent insulin-sensitizing yet weak adipogenic activity Mol. Cell 2001, 8, 737-747
40. Rossmann, M. G.; van Beek, C. G. Data processing Acta Crystallogr. Sect. D 1999, 55, 1631-1640
41. Collaborative computational project number 4. The CCP4 suits: programs for protein crystallography. Acta Crystallogr. Sect. D 1994, 50, 760-763.
42. Nolte, R. T.; Wisely, B.; Westin, S.; Cobb, J. E.; Lambert, M. H.; Kurokawa, R.; Rosenfield, M. G.; Willson, T. M.; Glass, C. K.; Milburn, M. V. Ligand binding and co-activator assembly of the peroxisome proliferators- activated receptor-γ Nature 1998, 395, 137-143
43. Brunger, A. T.; Adams, P. D.; Clore, G. M.; DeLano, W. L.; Gros, P.; Grosse-Kunstleve, R. W.; Jiang, J. S.; Kuszewski, J.; Nilges, M.; Pannu, N. S.; Read, R. J.; Rice, L. M.; Simonson, T.; Warren, G. L. Crystallography and NMR system: A new software suite for macromolecular structure determination Acta Crystallogr. Sect. D 1999, 54, 905-921
44. Rousell, A.; Fontecilla-Camps, J. C.; Cambillau, C. CRYStallize: a crystallographic symmetry display and handling subpackage in TOM/FRODO J. Mol. Graphics 1990, 8, 86-88
45. Morris, A. L.; MacArthur, M. W.; Hutchinson, E. G.; Thornton, J. M. Stereochemical quality of protein structure coordinates Proteins 1992, 12, 345-364