Structural insight into the crucial role of ligand chirality in the activation of PPARs by crystallographic methods

Current Topics in Medicinal Chemistry

Volumn 11, Issue 7, 2011, Pages 819-839

  Loiodice, F ^a   Pochetti, G ^b  

^a UNIVERSITY OF BARI   (Italy)

^b CNR   (Italy)

Author keywords

Chirality; Crystallographic methods; Fibrates; Nuclear receptors; Peroxisome proliferator activated receptors; Selective modulators; Stereoselectivity; Thiazolidinediones

Indexed keywords

2 [1 CARBOXY 2 [4 [2 (5 METHYL 2 PHENYL 4 OXAZOLYL)ETHOXY]PHENYL]ETHYLAMINO]BENZOIC ACID METHYL ESTER; 2,4 THIAZOLIDINEDIONE DERIVATIVE; AZETIDINONE DERIVATIVE; BALAGLITAZONE; BMS 631707; CIGLITAZONE; DARGLITAZONE; ENGLITAZONE; FARGLITAZAR; FIBRIC ACID DERIVATIVE; GW 409544; KY 021; LIGAND; N (2 BENZOYLPHENYL) O [2 (METHYL 2 PYRIDINYLAMINO)ETHYL]TYROSINE; NETOGLITAZONE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PIOGLITAZONE; RIVOGLITAZONE; ROSIGLITAZONE; TETRAHYDROISOQUINOLINE DERIVATIVE; TROGLITAZONE; TYROSINE DERIVATIVE; UNCLASSIFIED DRUG;

CHIRALITY; DRUG BINDING SITE; DRUG SELECTIVITY; DRUG STRUCTURE; FLUORESCENCE RESONANCE ENERGY TRANSFER; HYDROGEN BOND; HYDROPHOBICITY; MOLECULAR MODEL; REVIEW; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ANIMALS; BINDING SITES; CARDIOVASCULAR DISEASES; CRYSTALLIZATION; CRYSTALLOGRAPHY, X-RAY; DIABETES MELLITUS; FIBRIC ACIDS; HUMANS; LIGANDS; LIPID METABOLISM; MICE; OBESITY; ORGAN SPECIFICITY; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS; PROTEIN BINDING; PROTEIN ISOFORMS; RATS; STEREOISOMERISM; THIAZOLIDINEDIONES;

EID: 79953651662     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802611795165106     Document Type: Review

References (127)

1. Nuclear Receptors Nomenclature Committee. A unified nomenclature system for the nuclear receptor superfamily. Cell, 1999, 97, 161-163.
2. Feige, J. N.; Gelman, L.; Michalik, L.; Desvergne, B.; Wahli, W. From molecular action to physiological outputs: peroxisome prolif-erator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog. Lipid Res., 2006, 45, 120-159.
3. Desvergne, B.; Michalik, L.; Wahli, W. Transcriptional regulation of metabolism. Physiol. Rev., 2006, 86, 465-514.
4. Evans, R. M.; Barish, G. D.; Wang, Y. X. PPARs and the complex journey to obesity. Nat. Med., 2004, 10, 355-361.
5. Michalik, L.; Wahli, W. Involvement of PPAR nuclear receptors in tissue injury and wound repair. J. Clin. Invest., 2006, 116, 598-606.
6. Willson, T.; Brown, P. J.; Sternbach, D. D.; Henke, B. R. The PPARs: from orphan receptors to drug discovery. J. Med. Chem., 2000, 43, 527-550.
7. Elisaf, M. Effects of fibrates on serum metabolic parameters. Curr. Med. Res. Opin., 2002, 18, 269-276.
8. Staels, B.; Dallongeville, J.; Auwerx, J.; Schoonjans, K.; Leiters-dorf, E.; Fruchart, J. C. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation, 1998, 98, 2088-2093.
9. Campbell, I. W. The Clinical significance of PPAR gamma ago-nism. Curr. Mol. Med., 2005, 5, 349-363.
10. Sprecher, D. L. Lipids, lipoproteins, and peroxisome proliferator activated receptor-delta. Am. J. Cardiol., 2007, 100, n20-24.
11. Sprecher, D. L.; Massien, C.; Pearce, G.; Billin, A. N.; Perlstein, I.; Willson, T. M.; Hassall, D. G.; Ancellin, N.; Patterson, S. D.; Lobe, D. C.; Johnson, T. G. Triglyceride: high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome prolif-erator activated receptor delta agonist. Arterioscler. Thromb. Vasc. Biol., 2007, 27, 359-365.
12. Reilly, S. M.; Lee, C. H. PPAR delta as a therapeutic target in metabolic disease. FEBS Lett., 2008, 582, 26-31.
13. Madrazo, J. A.; Kelly, D. P. The PPAR trio: regulators of myocar-dial energy metabolism in health and disease. J. Mol. Cell. Car-diol., 2008, 44, 968-975.
14. Schmuth, M.; Jiang, Y. J.; Dubrac, S.; Elias, P. M.; Feingold, K. R. Thematic review series: skin lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology. J. Lipid Res., 2008, 49, 499-509.
15. Iwashita, A.; Muramatsu, Y.; Yamazaki, T.; Muramoto, M.; Kita, Y.; Yamazaki, S.; Mihara, K.; Moriguchi, A.; Matsuoka, N. Neuro-protective efficacy of the peroxisome proliferator-activated receptor delta-selective agonists in vitro and in vivo. J. Pharmacol. Exp. Ther., 2007, 320, 1087-1096.
16. Peters, J. M.; Hollingshead, H. E.; Gonzalez, F. J. Role of perox-isome-proliferator-activated receptor beta/delta (PPARbeta/delta) in gastrointestinal tract function and disease. Clin. Sci., (Lond) 2008, 115, 107-127.
17. Nolte, R. T.; Wisely, G. B.; Westin, S.; Cobb, J. E.; Lambert, M. H.; Kurokawa, R.; Rosenfeld, M. G.; Willson, T. M.; Glass, C. K.; Milburn, M. V. Ligand binding and co-activator assembly of the peroxisome proliferatoractivated receptor-gamma. Nature, 1998, 395, 137-143.
18. Gampe, Jr. R. T.; Montana, V. G.; Lambert, M. H.; Miller, A. B.; Bledsoe, R. K.; Milburn, M. V.; Kliewer, S. A.; Willson, T. M.; Xu, H. E. Asymmetry in the PPAR[gamma]/RXR[alpha] crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol. Cell, 2000, 5, 545-555.
19. Xu, H. E.; Lambert, M. H.; Montana, V. G.; Parks, D. J.; Blanch-ard, S. G.; Brown, P. J.; Sternbach, D. D.; Lehmann, J. M.; Wisely, G. B.; Willson, T. M.; Kliewer, S. A.; Milburn, M. V. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol. Cell, 1999, 3, 397-403.
20. Xu, H. E.; Lambert, M. H.; Montana, V. G.; Plunket, K. D.; Moore, L. B.; Collins, J. L.; Oplinger, J. A.; Kliewer, S. A.; Gampe, R. T. J.; McKee, D. D.; Moore, J. T.; Willson, T. M. Structural determinants of ligand binding selectivity between the peroxisome prolif-erator-activated receptors. Proc. Natl. Acad. Sci. USA, 2001, 98, 13919-13924.
21. Ebdrup, S.; Pettersson, I.; Rasmussen, H. B.; Deussen, H. J.; Frost, J. A.; Mortensen, S. B.; Fleckner, J.; Pridal, L.; Nygaard, L.; Sau-erberg, P. Synthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist ragaglitazar. J. Med. Chem., 2003, 46, 1306-1317.
22. Fyffe, S. A.; Alphey, M. S.; Buetow, L.; Smith, T. K.; Ferguson, M. A.; Sorensen, M. D.; Bjorkling, F.; Hunter, W. N. Recombinant human PPAR-beta/delta ligand-binding domain is locked in an activated conformation by endogenous fatty acids. J. Mol. Biol., 2006, 356, 1005-1013.
23. Barman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne, P. E. The protein data bank. Nucleic Acids Res., 2000, 28, 235-242.
24. Cronet, P.; Petersen, J. F.; Folmer, R.; Blomberg, N.; Sjöblom, K.; Karlsson, U.; Lindstedt, E. L.; Bamberg, K. Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family. Structure, 2001, 9, 699-706.
25. Xu, H. E.; Stanley, T. B.; Montana, V. G.; Lambert, M. H.; Shearer, B. G.; Cobb, J. E.; McKee, D. D.; Galardi, C. M.; Plunket, K. D.; Nolte, R. T.; Parks, D. J.; Moore, J. T.; Kliewer, S. A.; Will-son, T. M.; Stimmel, J. B. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Nature, 2002, 415, 813-817.
26. Lehmann, J. M.; Moore, L. B.; Smith-Oliver, T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A. An antidiabetic thiazolidinedi-one is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem., 1995, 270, 12953-12956.
27. Berger, J.; Bailey, P.; Biswas, C.; Cullinan, C. A.; Doebber, T. W.; Hayes, N. S.; Saperstein, R.; Smith, R. G.; Leibowitz, M. D. Thia-zolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology, 1996, 137, 4189-4195.
28. Willson, T. M.; Cobb, J. E.; Cowan, D. J.; Wiethe, R. W.; Correa, I. D.; Prakash, S. R.; Beck, K. D.; Moore, L. B.; Kliewer, S. A.; Lehmann, J. M. The structure-activity relationship between perox-isome proliferator-activated receptor gamma agonism and the anti-hyperglycemic activity of thiazolidinediones. J Med Chem., 1996, 39, 665-668.
29. Kanda, S.; Nakashima, R.; Takahashi, K.; Tanaka, J.; Ogawa, J.; Ogata, T.; Yachi, M.; Araki, K.; Ohsumi, J. Potent antidiabetic effects of rivoglitazone, a novel peroxisome proliferator-activated receptor-gamma agonist, in obese diabetic rodent models. J. Pharmacol. Sci., 2009, 111, 155-166.
30. Henriksen, K.; Byrjalsen, I.; Nielsen, R. H.; Madsen, A. N.; Larsen, L. K.; Christiansen, C.; Beck-Nielsen, H.; Karsdal, M. A. A comparison of glycemic control, water retention, and musculoskeletal effects of balaglitazone and pioglitazone in diet-induced obese rats. Eur. J. Pharmacol., 2009, 616, 340-345.
31. Larsen, P. J.; Lykkegaard, K.; Larsen, L. K.; Fleckner, J.; Sauer-berg, P.; Wassermann, K.; Wulff, E. M. Dissociation of antihyper-glycaemic and adverse effects of partial peroxisome proliferator-activated receptor (PPAR-gamma) agonist balaglitazone. Eur. J. Pharmacol., 2008, 596, 173-179.
32. Gale, E. A. Lessons from the glitazones: a story of drug development. Lancet, 2001, 357, 1870-1875.
33. Sohda, T.; Mizuno, K.; Kawamatsu, Y. Studies on antidiabetic agents. VI. Asymmetric transformation of (+/-)-5-[4-(1-methylcyclohexylmethoxy)benzyl]-2,4-thiazolidinedione (ciglitazone) with optically active 1-phenylethylamines. Chem. Pharm. Bull, 1984, 32, 4460-4465.
34. Parks, D. J.; Tomkinson, N. C. O.; Villeneuve, M. S.; Blanchard, S. G.; Willson, T. M. Differential activity of rosiglitazone enanti-omers at PPAR gamma. Bioorg. Med. Chem. Lett., 1998, 8, 3657-3658.
35. Nolte, R. T.; Wisely, G. B.; Westin, S.; Cobb, J. E.; Lambert, M. H.; Kurokawa, R.; Rosenfeld, M. G.; Willson, T. M.; Glass, C. K.; Milburn, M. V. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature, 1998, 395, 137-143.
36. Clark, D. A.; Goldstein, S. W.; Volkmann, R. A.; Eggler, J. F.; Holland, G. F.; Hulin, B.; Stevenson, R. W.; Kreutter, D. K.; Gibbs, E. M.; Krupp, M. N.; Merrigan, P.; Kelbaugh, P. L.; Andrews, E. G.; Tickner, D. L.; Suleske, R. T.; Lamphere, C. H.; Ra-jeckas, F. J.; Kappeler, W. H.; McDermott, R. E.; Hutson, N. J.; Johnson, M. R. Substituted dihydrobenzopyran and dihydrobenzo-furan thiazolidine-2,4-diones as hypoglycemic agents. J. Med. Chem., 1991, 34, 319-325.
37. Hulin, B.; McCarthy, P. A.; Gibbs, E. M. The glitazone family of antidiabetic agents. Curr. Pharm. Des., 1996, 2, 85-102.
38. Momose, Y.; Maekawa, T.; Yamano, T.; Kawada, M.; Odaka, H.; Ikeda, H.; Sohda, T. Novel 5-substituted 2,4-thiazolidinedione and 2,4-oxazolidinedione derivatives as insulin sensitizers with antidiabetic activities. J. Med. Chem., 2002, 45, 1518-1534.
39. Ferorelli, S.; Loiodice, F.; Longo, A.; Molfetta, A.; Tortorella, V.; Amoroso, R. Different behavior toward racemization in basic media from chiral analogs of clofibric acid, the active metabolite of the antilipidemic drug clofibrate. Chirality, 2000, 12, 697-704.
40. Henke, B. R.; Blanchard, S. G.; Brackeen, M. F.; Brown, K. K.; Cobb, J. E.; Collins, J. L.; Harrington, W. W. Jr; Hashim, M. A.; Hull-Ryde, E. A.; Kaldor, I.; Kliewer, S. A.; Lake, D. H.; Leesnit-zer, L. M.; Lehmann, J. M.; Lenhard, J. M.; Orband-Miller, L. A.; Miller, J. F.; Mook, R. A. Jr; Noble, S. A.; Oliver, W. Jr; Parks, D. J.; Plunket, K. D.; Szewczyk, J. R.; Willson, T. M. N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J. Med. Chem., 1998, 41, 5020-5036.
41. Collins, J. L.; Blanchard, S. G.; Boswell, G. E.; Charifson, P. S.; Cobb, J. E.; Henke, B. R.; Hull-Ryde, E. A.; Kazmierski, W. M.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J.; Lenhard, J. M.; Orband-Miller, L. A.; Gray-Nunez, Y.; Parks, D. J.; Plunkett, K. D.; Tong, W. Q. N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 2. Structure-activity relationship and optimization of the phenyl alkyl ether moiety. J. Med. Chem., 1998, 41, 5037-5054.
42. Cobb, J. E.; Blanchard, S. G.; Boswell, G. E.; Brown, K. K.; Charifson, P. S.; Cooper, J. P.; Collins, J. L.; Dezube, M.; Henke, B. R.; Hull-Ryde, E. A.; Lake, D. H.; Lenhard, J. M.; Oliver, W. Jr; Oplinger, J. A.; Pentti, M.; Parks, D. J.; Plunket, K. D.; Tong, W. Q. N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl sub-stituent. J. Med. Chem., 1998, 41, 5055-5069.
43. Gampe, R. T.; Montana, V. G.; Lambert, M. H.; Miller, A. B.; Bledsoe, R. K.; Milburn, M. V.; Kliewer, S. A.; Willson, T. M.; Xu, H. E. Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol. Cell, 2000, 5, 545-555.
44. Xu, H. E.; Lambert, M. H.; Montana, V. G.; Plunket, K. D.; Moore, L. B.; Collins, J. L.; Oplinger, J. A.; Kliewer, S. A.; Gampe, R. T.; McKee, D. D.; Moore, J. T.; Willson, T. M. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proc. Natl. Acad. Sci. USA, 2001, 98, 13919-13924.
45. Seber, S.; Ucak, S.; Basat, O.; Altuntas, Y. The effect of dual PPAR alpha/gamma stimulation with combination of rosiglitazone and fenofibrate on metabolic parameters in type 2 diabetic patients. Diabetes Res. Clin. Pract, 2006, 71, 52-58.
46. Li, P. P.; Shan, S.; Chen, Y. T.; Ning, Z. Q.; Sun, S. J.; Liu, Q.; Lu, X. P.; Xie, M. Z.; Shen, Z. F. The PPARalpha/gamma dual agonist chiglitazar improves insulin resistance and dyslipidemia in MSG obese rats. Br. J. Pharmacol, 2006, 148, 610-618.
47. Xu, C; Wang, L.; Liu, H.; Zhou, X.; Cao, Y.; Li, S. C333H, a novel PPARa/y dual agonist, has beneficial effects on insulin resistance and lipid metabolism. Acta Pharmacol. Sin., 2006, 27, 223-228.
48. Liu, K. G.; Lambert, M. H.; Ayscue, A. H.; Henke, B. R.; Leesnit-zer, L. M.; Oliver, W. R. Jr; Plunket, K. D.; Xu, H. E.; Sternbach, D. D.; Willson, T. M. Synthesis and biological activity of L-tyrosine-based PPARgamma agonists with reduced molecular weight. Bioorg. Med. Chem. Lett., 2001, 11, 3111-3113.
49. Casimiro-Garcia, A.; Bigge, C. F.; Davis, J. A.; Padalino, T.; Pu-laski, J.; Ohren, J. F.; McConnell, P.; Kane, C. D.; Royer, L. J.; Stevens, K. A.; Auerbach, B. J.; Collard, W. T.; McGregor, C.; Fakhoury, S. A.; Schaum, R. P.; Zhou, H. Effects of modifications of the linker in a series of phenylpropanoic acid derivatives: Synthesis, evaluation as PPARalpha/gamma dual agonists, and X-ray crystallographic studies. Bioorg. Med. Chem., 2008, 16, 4883-4907.
50. Casimiro-Garcia, A.; Bigge, C. F.; Davis, J. A.; Padalino, T.; Pu-laski, J.; Ohren, J. F.; McConnell, P.; Kane, C. D.; Royer, L. J.; Stevens, K. A.; Auerbach, B. J.; Collard, W. T.; McGregor, C.; Song, K. Synthesis and evaluation of novel alpha-heteroaryl-phenylpropanoic acid derivatives as PPARalpha/gamma dual agonists. Bioorg. Med. Chem., 2009, 17, 7113-7125.
51. Azukizawa, S.; Kasai, M.; Takahashi, K.; Miike, T.; Kunishiro, K.; Kanda, M.; Mukai, C.; Shirahase, H. Synthesis and biological evaluation of (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: a novel series of PPAR gamma agonists. Chem. Pharm. Bull., 2008, 56, 335-345.
52. Wang, W.; Devasthale, P.; Farrelly, D.; Gu, L.; Harrity, T.; Cap, M.; Chu, C.; Kunselman, L.; Morgan, N.; Ponticiello, R.; Zebo, R.; Zhang, L.; Locke, K.; Lippy, J.; O'Malley, K.; Hosagrahara, V.; Zhang, L.; Kadiyala, P.; Chang, C.; Muckelbauer, J.; Doweyko, A. M.; Zahler, R.; Ryono, D.; Hariharan, N.; Cheng, P. T. W. Discovery of azetidinone acids as conformationally-constrained dual PPARalpha/gamma agonists. Bioorg. Med. Chem. Lett., 2008, 18, 1939-1944.
53. Xu, H. E.; Stanley, T. B.; Montana, V. G.; Lambert, M. H.; Shearer, B. G.; Cobb, J. E.; McKee, D. D.; Galardi, C. M.; Plunket, K. D.; Nolte, R. T.; Parks, D. J.; Moore, J. T.; Kliewer, S. A.; Will-son, T. M.; Stimmel, J. B. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Nature, 2002, 415, 813-817.
54. Stanley, T. B.; Leesnitzer, L. M.; Montana, V. G.; Galardi, C. M.; Lambert, M. H.; Holt, J. A.; Xu, H. E.; Moore, L. B.; Blanchard, S. G.; Stimmel, J. B. Subtype specific effects of peroxisome prolifera-tor-activated receptor ligands on corepressor affinity. Biochemistry, 2003, 42, 9278-9287.
55. Trump, R. P.; Cobb, J. E.; Shearer, B. G.; Lambert, M. H.; Nolte, R. T.; Willson, T. M.; Buckholz, R. G.; Zhao, S. M.; Leesnitzer, L. M.; Iannone, M. A.; Pearce, K. H.; Billin, A. N.; Hoekstra, W. J. Co-crystal structure guided array synthesis of PPARgamma inverse agonists. Bioorg. Med. Chem. Lett., 2007, 17, 3916-3920.
56. Murakami, K.; Tobe, K.; Ide, T.; Mochizuki, T.; Ohashi, M.; Akanuma, Y.; Yazaki, Y.; Kadowaki, T. A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats. Diabetes, 1998, 47, 1841-1847.
57. Nomura, M.; Tanase, T.; Ide, T.; Tsunoda, M.; Suzuki, M.; Uchiki, H.; Murakami, K.; Miyachi, H. Design, synthesis, and evaluation of substituted phenylpropanoic acid derivatives as human peroxisome proliferator activated receptor activators. Discovery of potent and human peroxisome proliferator activated receptor alpha subtype-selective activators. J. Med. Chem., 2003, 46, 3581-3599.
58. Kasuga, J.; Makishima, M.; Hashimoto, Y.; Miyachi, H. Design and synthesis of substituted phenylpropanoic acid derivatives as human peroxisome proliferator-activated receptor alpha/delta dual agonists. Bioorg. Med. Chem. Lett., 2006, 16, 554-558.
59. Kasuga, J.; Yamasaki, D.; Araya, Y.; Nakagawa, A.; Makishima, M.; Doi, T.; Hashimoto, Y.; Miyachi, H. Design, synthesis, and evaluation of a novel series of alpha-substituted phenylpropanoic acid derivatives as human peroxisome proliferator-activated receptor (PPAR) alpha/delta dual agonists for the treatment of metabolic syndrome. Bioorg. Med. Chem., 2006, 14, 8405-8414.
60. Kasuga, J.; Nakagome, I.; Aoyama, A.; Sako, K.; Ishizawa, M.; Ogura, M.; Makishima, M.; Hirono, S.; Hashimoto, Y.; Miyachi, H. Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) delta-selective agonists. Bioorg. Med. Chem., 2007, 15, 5177-5190.
61. Kasuga, J.; Oyama, T.; Nakagome, I.; Makishima, M.; Hirono, S.; Morikawa, K.; Hashimoto, Y.; Miyachi, H. Determination of the critical amino acids involved in the peroxisome proliferator-activated receptor (PPAR) delta selectivity of phenylpropanoic acid-derived agonists. ChemMedChem, 2008, 3, 1662-1666.
62. Feldman, P. L.; Lambert, M. H.; Henke, B. R. PPAR modulators and PPAR pan agonists for metabolic diseases: the next generation of drugs targeting peroxisome proliferator-activated receptors? Curr. Top. Med. Chem., 2008, 8, 728-749.
63. Oyama, T.; Toyota, K.; Waku, T.; Hirakawa, Y.; Nagasawa, N.; Kasuga, J.; Hashimoto, Y.; Miyachi, H.; Morikawa, K. Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures. Acta Crystallogr. D Biol. Crystallogr, 2009, 65, 786-795.
64. Kasuga, J.; Yamasaki, D.; Ogura, K.; Shimizu, M.; Sato, M.; Makishima, M.; Doi, T.; Hashimoto, Y.; Miyachi, H. SAR-oriented discovery of peroxisome proliferator-activated receptor pan agonist with a 4-adamantylphenyl group as a hydrophobic tail. Bioorg. Med. Chem. Lett., 2008, 18, 1110-1115.
65. Lowe, D. B.; Bifulco, N.; Bullock, W. H.; Claus, T.; Coish, P.; Dai, M.; Dela Cruz, F. E.; Dickson, D.; Fan, D.; Hoover-Litty, H.; Li, T.; Ma, X.; Mannelly, G.; Monahan, M. K.; Muegge, I.; O'Connor, S.; Rodriguez, M.; Shelekhin, T.; Stolle, A.; Sweet, L.; Wang, M.; Wang, Y.; Zhang, C; Zhang, H. J.; Zhang, M.; Zhao, K.; Zhao, Q.; Zhu, J.; Zhu, L.; Tsutsumi, M. Substituted indanylacetic acids as PPAR-alpha-gamma activators. Bioorg. Med. Chem. Lett., 2006, 16, 297-301.
66. Hulin, B.; Newton, L. S.; Lewis, D. M.; Genereux, P. E.; Gibbs, E. M.; Clark, D. A. Hypoglycemic activity of a series of alpha-alkylthio and alpha-alkoxy carboxylic acids related to ciglitazone. J. Med. Chem., 1996, 39, 3897-3907.
67. Buckle, D. R.; Cantello, B. C. C; Cawthorne, M. A.; Coyle, P. J.; Dean, D. K.; Faller, A.; Haigh, D.; Hindley, R. M.; Jefcott, L. J.; Lister, C. A.; Pinto, I. L.; Rami, H. K.; Smith, D. G.; Smith, S. A. Non thiazolidinedione antihyperglycaemic agents. 1: a-Heteroatom substituted p-phenylpropanoic acids. Bioorg. Med. Chem. Lett., 1996, 6, 2121-2126.
68. Buckle, D. R.; Cantello, B. C. C; Cawthorne, M. A.; Coyle, P. J.; Dean, D. K.; Faller, A.; Haigh, D.; Hindley, R. M.; Jefcott, L. J.; Lister, C. A.; Pinto, I. L.; Rami, H. K.; Smith, D. G.; Smith, S. A. Non thiazolidinedione antihyperglycaemic agents. 2: a-Carbon substituted p-phenylpropanoic acids. Bioorg. Med. Chem. Lett., 1996, 6, 2127-2130.
69. Young, P. W.; Buckle, D. R.; Cantello, B. C. C; Chapman, H.; Clapham, J. C; Coyle, P. J.; Haigh, D.; Hindley, R. M.; Holder, J. C; Kallender, H.; Latter, A. J.; Lawrie, K. W. M.; Mossakowska, D.; Murphy, G. J.; Roxbee Cox, L.; Smith, S. A. Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodi-nated ligand for peroxisomal proliferator-activated receptor gamma. J. Pharmacol. Exp. Ther., 1998, 284,751-759.
70. Haigh, D.; Allen, G.; Birrell, H. C; Bucale, D. R.; Cantello, B. C. C; Eggleston, D. S.; Haltiwanger, R. C; Holder, J. C; Lister, C. A.; Pinto, I. L.; Rami, H. K.; Sime, J. T.; Smith, S. A.; Sweeney, J. D. Non-thiazolidinedione antihyperglycaemic agents. Part 3: The effects of stereochemistry on the potency of alpha-methoxy-beta-phenylpropanoic acids. Bioorg. Med. Chem., 1999, 7, 821-830.
71. Liu, K. G.; Smith, J. S.; Ayscue, A. H.; Henke, B. R.; Lambert, M. H.; Leesnitzer, L. M.; Plunket, K. D.; Willson, T. M.; Sternbach, D. D. Identification of a series of oxadiazole-substituted alpha-isopropoxy phenylpropanoic acids with activity on PPARalpha, PPARgamma, and PPARdelta. Bioorg. Med. Chem. Lett., 2001, 11, 2385-2388.
72. Cronet, P.; Petersen, J. F.; Folmer, R.; Blomberg, N.; Sjöblom, K.; Karlsson, U.; Lindstedt, E. L.; Bamberg, K. Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family. Structure, 2001, 9, 699-706.
73. Lohray, B. B.; Lohray, V. B.; Bajji, A. C; Kalchar, S.; Poondra, R. R.; Padakanti, S.; Chakrabarti, R.; Vikramadithyan, R. K.; Misra, P.; Juluri, S.; Mamidi, N. V.; Rajagopalan, R. (-)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid [(-)DRF 2725]: a dual PPAR agonist with potent antihyperglycemic and lipid modulating activity. J. Med. Chem., 2001, 44, 2675-2678.
74. Sauerberg, P.; Pettersson, I.; Jeppesen, L.; Bury, P. S.; Mogensen, J. P.; Wassermann, K.; Brand, C. L.; Sturis, J.; Wöldike, H. F.; Fleckner, J.; Andersen, A. S.; Mortensen, S. B.; Svensson, L. A.; Rasmussen, H. B.; Lehmann, S. V.; Polivka, Z.; Sindelar, K.; Pana-jotova, V.; Ynddal, L.; Wulff, E. M. Novel tricyclic-alpha-alkyloxyphenylpropionic acids: dual PPARalpha/gamma agonists with hypolipidemic and antidiabetic activity. J. Med. Chem., 2002, 45, 789-804.
75. Ebdrup, S.; Pettersson, I.; Rasmussen, H. B.; Deussen, H. J.; Frost Jensen, A.; Mortensen, S. B.; Fleckner, J.; Pridal, L.; Nygaard, L.; Sauerberg, P. Synthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist ragaglitazar. J. Med. Chem., 2003, 46, 1306-1317.
76. Mogensen, J. P.; Jeppesen, L.; Bury, P. S.; Pettersson, I.; Fleckner, J.; Nehlin, J.; Frederiksen, K. S.; Albrektsen, T.; Din, N.; Mort-ensen, S. B.; Svensson, L. A.; Wassermann, K.; Wulff, E. M.; Ynddal, L.; Sauerberg, P. Design and synthesis of novel PPARal-pha/gamma/delta triple activators using a known PPARal-pha/gamma dual activator as structural template. Bioorg. Med. Chem. Lett., 2003, 13, 257-260.
77. Sauerberg, P.; Bury, P. S.; Mogensen, J. P.; Deussen, H. J.; Petters-son, I.; Fleckner, J.; Nehlin, J.; Frederiksen, K. S.; Albrektsen, T.; Din, N.; Svensson, L. A.; Ynddal, L.; Wulff, E. M.; Jeppesen, L. Large dimeric ligands with favorable pharmacokinetic properties and peroxisome proliferator-activated receptor agonist activity in vitro and in vivo. J. Med. Chem., 2003, 46, 4883-4894.
78. Sauerberg, P.; Mogensen, J. P.; Jeppesen, L.; Svensson, L. A.; Fleckner, J.; Nehlin, J.; Wulff, E. M.; Pettersson, I. Structure-activity relationships of dimeric PPAR agonists. Bioorg. Med. Chem. Lett., 2005, 15, 1497-1500.
79. Sauerberg, P.; Mogensen, J. P.; Jeppesen, L.; Bury, P. S.; Fleckner, J.; Olsen, G. S.; Jeppesen, C. B.; Wulff, E. M.; Pihera, P.; Havra-nek, M.; Polivka, Z.; Pettersson, I. Design of potent PPARalpha agonists. Bioorg. Med. Chem. Lett., 2007, 17, 3198-3202.
80. Reifel-Miller, A.; Otto, K.; Hawkins, E.; Barr, R.; Bensch, W. R.; Bull, C.; Dana, S.; Klausing, K.; Martin, J. A.; Rafaeloff-Phail, R.; Rafizadeh-Montrose, C.; Rhodes, G.; Robey, R.; Rojo, I.; Rungta, D.; Snyder, D.; Wilbur, K.; Zhang, T.; Zink, R.; Warshawsky, A.; Brozinick, J. T. A peroxisome proliferator-activated receptor alpha/gamma dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia. Mol. Endocrinol., 2005, 19, 1593-1605.
81. Martín, J. A.; Brooks, D. A.; Prieto, L.; González, R.; Torrado, A.; Rojo, I.; López de Uralde, B.; Lamas, C.; Ferreto, R.; Dolores Martín-Ortega, M.; Agejas, J.; Parra, F.; Rizzo, J. R.; Rhodes, G. A.; Robey, R. L.; Alt, C. A.; Wendel, S. R.; Zhang, T. Y.; Reifel-Miller, A.; Montrose-Rafizadeh, C.; Brozinick, J. T.; Hawkins, E.; Misener, E. A.; Briere, D. A.; Ardecky, R.; Fraser, J. D.; War-shawsky, A. M. 2-Alkoxydihydrocinnamates as PPAR agonists. Activity modulation by the incorporation of phenoxy substituents. Bioorg. Med. Chem. Lett., 2005, 15, 51-55.
82. Humphries, P. S.; Almaden, J. V.; Barnum, S. J.; Carlson, T. J.; Do, Q. Q.; Fraser, J. D.; Hess, M.; Kim, Y. H.; Ogilvie, K. M.; Sun, S. Pyridine-2-propanoic acids: Discovery of dual PPARal-pha/gamma agonists as antidiabetic agents. Bioorg. Med. Chem. Lett., 2006, 16, 6116-6119.
83. Humphries, P. S.; Bailey, S.; Almaden, J. V.; Barnum, S. J.; Carlson, T. J.; Christie, L. C.; Do, Q. Q.; Fraser, J. D.; Hess, M.; Kel-lum, J.; Kim, Y. H.; McClellan, G. A.; Ogilvie, K. M.; Simmons, B. H.; Skalitzky, D.; Sun, S.; Wilhite, D.; Zehnder, L. R. Pyridine-3-propanoic acids: Discovery of dual PPARalpha/gamma agonists as antidiabetic agents. Bioorg. Med. Chem. Lett., 2006, 16, 6120-6123.
84. Kuhn, B.; Hilpert, H.; Benz, J.; Binggeli, A.; Grether, U.; Humm, R.; Märki, H. P.; Meyer, M.; Mohr, P. Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists. Bioorg. Med. Chem. Lett., 2006, 16, 4016-4020.
85. Grether, U.; Bénardeau, A.; Benz, J.; Binggeli, A.; Blum, D.; Hil-pert, H.; Kuhn, B.; Märki, H. P.; Meyer, M.; Mohr, P.; Püntener, K.; Raab, S.; Ruf, A.; Schlatter, D. Design and biological evaluation of novel, balanced dual PPARalpha/gamma agonists. ChemMedChem, 2009, 4, 951-956.
86. Bénardeau, A.; Benz, J.; Binggeli, A.; Blum, D.; Boehringer, M.; Grether, U.; Hilpert, H.; Kuhn, B.; Märki, H. P.; Meyer, M.; Püntener, K.; Raab, S.; Ruf, A.; Schlatter, D.; Mohr, P. Aleglitazar, a new, potent, and balanced dual PPARalpha/gamma agonist for the treatment of type II diabetes. Bioorg. Med. Chem. Lett., 2009, 19, 2468-2473.
87. Kim, N. J.; Lee, K. O.; Koo, B. W.; Li, F.; Yoo, J. K.; Park, H. J.; Min, K. H.; Lim, J. I.; Kim, M. K.; Kim, J. K.; Suh, Y. G. Design, synthesis, and structure-activity relationship of carbamate-tethered aryl propanoic acids as novel PPARalpha/gamma dual agonists. Bioorg. Med. Chem. Lett., 2007, 17, 3595-3598.
88. Kim, M. K.; Chae, Y. N.; Son, M. H.; Kim, S. H.; Kim, J. K.; Moon, H. S.; Park, C. S.; Bae, M. H.; Kim, E.; Han, T.; Choi, H. H.; Shin, Y. A.; Ahn, B. N.; Lee, C. H.; Lim, J. I.; Shin, C. Y. PAR-5359, a well-balanced PPARalpha/gamma dual agonist, exhibits equivalent antidiabetic and hypolipidemic activities in vitro and in vivo. Eur. J. Pharmacol., 2008, 595, 119-125.
89. Kim, M. K.; Chae, Y. N.; Kim, H. S.; Choi, S. H.; Son, M. H.; Kim, S. H.; Kim, J. K.; Moon, H. S.; Park, S. K.; Shin, Y. A.; Kim, J. G.; Lee, C. H.; Lim, J. I.; Shin, C. Y. PAR-1622 is a selective peroxisome proliferator-activated receptor gamma partial activator with preserved antidiabetic efficacy and broader safety profile for fluid retention. Arch. Pharm. Res., 2009, 32, 721-727.
90. Suh, Y. G.; Kim, N. J.; Koo, B. W.; Lee, K. O.; Moon, S. H.; Shin, D. H.; Jung, J. W.; Paek, S. M.; Chang, D. J.; Li, F.; Kang, H. J.; Le, T. V. T.; Chae, Y. N.; Shin, C. Y.; Kim, M. K.; Lim, J. I.; Ryu, J. S.; Park, H. J. Design, synthesis, and biological evaluation of novel constrained meta-substituted phenyl propanoic acids as per-oxisome proliferator-activated receptor alpha and gamma dual agonists. J. Med. Chem., 2008, 51, 6318-6333.
91. Rangwala, S. M.; O'Brien, M. L.; Tortorella, V.; Longo, A.; Loio-dice, F.; Noonan, D. J.; Feller, D. R. Stereoselective effects of chiral clofibric acid analogs on rat peroxisome proliferator-activated receptor alpha (rPPAR alpha) activation and peroxisomal fatty acid beta-oxidation. Chirality, 1997, 9, 37-47.
92. Adams, A. D.; Hu, Z.; von Langen, D.; Dadiz, A.; Elbrecht, A.; MacNaul, K. L.; Berger, J. P.; Zhou, G.; Doebber, T. W.; Meurer, R.; Forrest, M. J.; Moller, D. E.; Jones, A. B. O-arylmandelic acids as highly selective human PPAR alpha/gamma agonists. Bioorg. Med. Chem. Lett., 2003, 13, 3185-3190.
93. Shi, G. Q.; Dropinski, J. F.; McKeever, B. M.; Xu, S.; Becker, J. W.; Berger, J. P.; MacNaul, K. L.; Elbrecht, A.; Zhou, G.; Doeb-ber, T. W.; Wang, P.; Chao, Y. S.; Forrest, M.; Heck, J. V.; Moller, D. E.; Jones, A. B. Design and synthesis of alpha-aryloxyphenylacetic acid derivatives: a novel class of PPARal-pha/gamma dual agonists with potent antihyperglycemic and lipid modulating activity. J. Med. Chem., 2005, 48, 4457-4468.
94. Aronow, W. S.; Harding, P. R.; Khursheed, M.; Vangrow, J. S.; Papageorge's, N. P.; Mays, J. Effect of halofenate on serum lipids. Clin. Pharmacol. Ther., 1973, 14, 358-365.
95. Aronow, W. S.; Harding, P. R.; Khursheed, M.; Vangrow, J. S.; Papageorge's, N. P. Effect of halofenate on serum uric acid. Clin. Pharmacol. Ther., 1973, 14, 371-373.
96. Chandalia, A.; Clarke, H. J.; Clemens, L. E.; Pandey, B.; Vicena, V.; Lee, P.; Lavan, B. E.; Gregoire, F. M. MBX-102/JNJ39659100, a novel non-TZD selective partial PPAR-gamma agonist lowers triglyceride independently of PPAR-alpha activation. PPAR Res., 2009, Article ID 706852.
97. 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.
98. Allen, T.; Zhang, F.; Moodie, S. A.; Clemens, L. E.; Smith, A.; Gregoire, F.; Bell, A.; Muscat, G. E.; Gustafson, T. A. Halofenate is a selective peroxisome proliferator-activated receptor gamma modulator with antidiabetic activity. Diabetes 2006, 55, 2523-2533.
99. Luskey, K. L.; Luo, J. Use of (-)-(3-trihalomethylphenoxy)-(4-halophenyl)acetic acid derivatives for treatment of insulin resistance, Type 2 diabetes and hyperlipidemia. U.S. Patent 6262118, Jul 17, 2001.
100. Zhu, Y.; Cheng, P.; Chen, X.; Ma, J.; Zhao, Z. Process for the stereoselective preparation of (-)-halofenate and derivatives thereof. U.S. Patent 0072858, Mar 29, 2007.
101. Pinelli, A.; Godio, C.; Laghezza, A.; Mitro, N.; Fracchiolla, G.; Tortorella, V.; Lavecchia, A.; Novellino, E.; Fruchart, J.-C.; Staels, B.; Crestani, M.; Loiodice, F. Synthesis, biological evaluation, and molecular modeling investigation of new chiral fibrates with PPARalpha and PPARgamma agonist activity. J. Med. Chem., 2005, 48, 5509-5519.
102. Fracchiolla, G.; Laghezza, A.; Piemontese, L.; Carbonara, G.; Lavecchia, A.; Tortorella, P.; Crestani, M.; Novellino, E.; Loiodice, F. Synthesis, biological evaluation, and molecular modeling investigation of chiral phenoxyacetic acid analogues with PPARalpha and PPARgamma agonist activity. ChemMedChem, 2007, 2, 641-654.
103. Fracchiolla, G.; Lavecchia, A.; Laghezza, A.; Piemontese, L.; Trisolini, R.; Carbonara, G.; Tortorella, P.; Novellino, E.; Loiodice, F. Synthesis, biological evaluation, and molecular modeling investigation of chiral 2-(4-chloro-phenoxy)-3-phenyl-propanoic acid derivatives with PPARalpha and PPARgamma agonist activity. Bioorg. Med. Chem., 2008, 16, 9498-9510.
104. Montanari, R.; Saccoccia, F.; Scotti, E.; Crestani, M.; Godio, C.; Gilardi, F.; Loiodice, F.; Fracchiolla, G.; Laghezza, A.; Tortorella, P.; Lavecchia, A.; Novellino, E.; Mazza, F.; Aschi, M.; Pochetti, G. Crystal structure of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could be exploited for drug design. J. Med. Chem., 2008, 51, 7768-7776.
105. Fracchiolla, G.; Laghezza, A.; Piemontese, L.; Tortorella, P.; Mazza, F.; Montanari, R.; Pochetti, G.; Lavecchia, A.; Novellino, E.; Pierno, S.; Conte Camerino, D.; Loiodice, F. New 2-aryloxy-3-phenyl-propanoic acids as peroxisome proliferator-activated receptors alpha/gamma dual agonists with improved potency and reduced adverse effects on skeletal muscle function. J. Med. Chem., 2009, 52, 6382-6393.
106. Xu, Y.; Rito, C. J.; Etgen, G. J.; Ardecky, R. J.; Bean, J. S.; Bensch, W. R.; Bosley, J. R.; Broderick, C. L.; Brooks, D. A.; Dominianni, S. J.; Hahn, P. J.; Liu, S.; Mais, D. E.; Montrose-Rafizadeh, C.; Ogilvie, K. M.; Oldham, B. A.; Peters, M.; Rungta, D. K.; Shuker, A. J.; Stephenson, G. A.; Tripp, A. E.; Wilson, S. B.; Winneroski, L. L.; Zink, R.; Kauffman, R. F.; McCarthy, J. R. Design and synthesis of alpha-aryloxy-alpha-methylhydrocinnamic acids: a novel class of dual peroxisome proliferator-activated receptor alpha/gamma agonists. J. Med. Chem., 2004, 47, 2422-2425.
107. Takamura, M.; Sakurai, M.; Yamada, E.; Fujita, S.; Yachi, M.; Takagi, T.; Isobe, A.; Hagisawa, Y.; Fujiwara, T.; Yanagisawa, H. Synthesis and biological activity of novel alpha-substituted beta-phenylpropionic acids having pyridin-2-ylphenyl moiety as anti-hyperglycemic agents. Bioorg. Med. Chem., 2004, 12, 2419-2439.
108. Koyama, H.; Miller, D. J.; Boueres, J. K.; Desai, R. C.; Jones, A. B.; Berger, J. P.; MacNaul, K. L.; Kelly, L. J.; Doebber, T. W.; Wu, M. S.; Zhou, G.; Wang, P. R.; Ippolito, M. C.; Chao, Y. S.; Agrawal, A. K.; Franklin, R.; Heck, J. V.; Wright, S. D.; Moller, D. E.; Sahoo, S.P. (2R)-2-ethylchromane-2-carboxylic acids: discovery of novel PPARalpha/gamma dual agonists as antihyperglyce-mic and hypolipidemic agents. J. Med. Chem., 2004, 47, 3255-3263.
109. Koyama, H.; Boueres, J. K.; Miller, D. J.; Berger, J. P.; MacNaul, K. L.; Wang, P. R.; Ippolito, M. C.; Wright, S. D.; Agrawal, A. K.; Moller, D. E.; Sahoo, S.P. (2R)-2-methylchromane-2-carboxylic acids: discovery of selective PPARalpha agonists as hypolipidemic agents. Bioorg. Med. Chem. Lett., 2005, 15, 3347-3351.
110. Shi, G. Q.; Dropinski, J. F.; Zhang, Y.; Santini, C.; Sahoo, S. P.; Berger, J. P.; Macnaul, K. L.; Zhou, G.; Agrawal, A.; Alvaro, R.; Cai, T. Q.; Hernandez, M.; Wright, S. D.; Moller, D. E.; Heck, J. V.; Meinke, P. T. Novel 2,3-dihydrobenzofuran-2-carboxylic acids: highly potent and subtype-selective PPARalpha agonists with potent hypolipidemic activity. J. Med. Chem., 2005, 48, 5589-5599.
111. Desai, R. C.; Metzger, E.; Santini, C.; Meinke, P. T.; Heck, J. V.; Berger, J. P.; MacNaul, K. L.; Cai, T. Q.; Wright, S. D.; Agrawal, A.; Moller, D. E.; Sahoo, S. P. Design and synthesis of potent and subtype-selective PPARalpha agonists. Bioorg. Med. Chem. Lett., 2006, 16, 1673-1678.
112. Yamazaki, Y.; Abe, K.; Toma, T.; Nishikawa, M.; Ozawa, H.; Okuda, A.; Araki, T.; Oda, S.; Inoue, K.; Shibuya, K.; Staels, B.; Fruchart, J.-C. Design and synthesis of highly potent and selective human peroxisome proliferator-activated receptor alpha agonists. Bioorg. Med. Chem. Lett., 2007, 17, 4689-4693.
113. Pochetti, G.; Godio, C.; Mitro, N.; Caruso, D.; Galmozzi, A.; Scu-rati, S.; Loiodice, F.; Fracchiolla, G.; Tortorella, P.; Laghezza, A.; Lavecchia, A.; Novellino, E.; Mazza, F.; Crestani, M. Insights into the mechanism of partial agonism: crystal structures of the perox-isome proliferator-activated receptor gamma ligand-binding domain in the complex with two enantiomeric ligands. J. Biol. Chem., 2007, 282, 17314-17324.
114. Lehmann, J. M.; Lenhard, J. M.; Oliver, B. B.; Ringold, G. M.; Kliewer, S. A. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem., 1997, 272, 3406-3410.
115. 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.; Mosley, R.; Surwit, R. S.; Moller, D. E. Distinct properties and advantages of a novel perox-isome proliferator-activated protein [gamma] selective modulator. Mol. Endocrinol., 2003, 17, 662-676.
116. Henke, B. R.; Adkison, K. K.; Blanchard, S. G.; Leesnitzer, L. M.; Mook, R. A.; Plunket, K. D.; Ray, J. A.; Roberson, C.; Unwalla, R.; Willson, T. M. Synthesis and biological activity of a novel series of indole-derived PPARgamma agonists. Bioorg. Med. Chem. Lett., 1999, 9, 3329-3334.
117. 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. Ben-zoyl 2-methyl indoles as selective PPARgamma modulators. Bioorg. Med. Chem. Lett., 2005, 15, 357-362.
118. Liu, K.; Black, R. M.; Acton, J. J.; Mosley, R.; Debenham, S.; Abola, R.; Yang, M.; Tschirret-Guth, R.; Colwell, L.; Liu, C.; Wu, M.; Wang, C. F.; MacNaul, K. L.; McCann, M. E.; Moller, D. E.; Berger, J. P.; Meinke, P. T.; Jones, A. B.; Wood, H. B. Selective PPARgamma modulators with improved pharmacological profiles. Bioorg. Med. Chem. Lett., 2005, 15, 2437-2440.
119. Debenham, S. D.; Chan, A.; Lau, F. W.; Liu, W.; Wood, H. B.; Lemme, K.; Colwell, L.; Habulihaz, B.; Akiyama, T. E.; Einstein, M.; Doebber, T. W.; Sharma, N.; Wang, C. F.; Wu, M.; Berger, J. P.; Meinke, P. T. Highly functionalized 7-azaindoles as selective PPAR gamma modulators. Bioorg. Med. Chem. Lett., 2008, 18, 4798-4801.
120. Bruning, J. B.; Chalmers, M. J.; Prasad, S.; Busby, S. A.; Kame-necka, T. M.; He, Y.; Nettles, K. W.; Griffin, P. R. Partial agonists activate PPARgamma using a helix 12 independent mechanism. Structure, 2007, 15, 1258-1271.
121. 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 peroxisome proliferator-activated receptor gamma ligands with Tyr473 is a physical basis for their unique biological activities. Mol. Pharmacol., 2008, 73, 62-74.
122. 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 gamma (PPARgamma) modulator with balanced PPARalpha activity for the treatment of type 2 diabetes and dyslipidemia. J. Med. Chem., 2009, 52, 4443-4453.
123. Acton, J. J.; Akiyama, T. E.; Chang, C. H.; Colwell, L.; De-benham, 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 (2R)-2-(3-{3-[(4-methoxyphenyl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl}phenoxy)butanoic acid (MK-0533): a novel selective peroxisome proliferator-activated receptor gamma 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, 3846-3854.
124. Rau, O.; Syha, Y.; Zettl, H.; Kock, M.; Bock, A.; Schubert-Zsilavecz, M. Alpha-alkyl substituted pirinixic acid derivatives as potent dual agonists of the peroxisome proliferator activated receptor alpha and gamma. Arch. Pharm., (Weinheim) 2008, 341, 191-195.
125. Zettl, H.; Steri, R.; Lämmerhofer, M.; Schubert-Zsilavecz, M. Discovery of a novel class of 2-mercaptohexanoic acid derivatives as highly active PPARalpha agonists. Bioorg. Med. Chem. Lett., 2009, 19, 4421-4426.
126. Zettl, H.; Dittrich, M.; Steri, R.; Proschak, E.; Rau, O.; Steinhilber, D.; Schneider, G.; Lämmerhofer, M.; Schubert-Zsilavecz M. Novel pirinixic acids as PPARalpha preferential dual PPARalpha/gamma agonists. QSAR Comb. Sci., 2009, 28, 576-586.
127. Giampietro, L.; Ammazzalorso, A.; Giancristofaro, A.; Lannutti, F.; Bettoni, G.; De Filippis, B.; Fantacuzzi, M.; Maccallini, C.; Petruzzelli, M.; Morgano, A.; Moschetta, A.; Amoroso, R. Synthesis and biological evaluation of 2-heteroarylthioalkanoic acid analogues of clofibric acid as peroxisome proliferator-activated receptor alpha agonists. J. Med. Chem., 2009, 52, 6224-6232.