Peroxisome proliferator-activated receptors (PPARs) have multiple binding points that accommodate ligands in various conformations: Phenylpropanoic acid-type PPAR ligands bind to PPAR in different conformations, depending on the subtype

Journal of Medicinal Chemistry

Volumn 55, Issue 2, 2012, Pages 893-902

  Kuwabara, Naoyuki ^a   Oyama, Takuji ^b   Tomioka, Daisuke ^c   Ohashi, Masao ^d   Yanagisawa, Junn ^e   Shimizu, Toshiyuki ^a   Miyachi, Hiroyuki ^d  

^a UNIVERSITY OF TOKYO   (Japan)

^b OSAKA UNIVERSITY   (Japan)

^c YOKOHAMA CITY UNIVERSITY   (Japan)

^d OKAYAMA UNIVERSITY   (Japan)

^e UNIVERSITY OF TSUKUBA   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

2 [3 [[4 (1 ADAMANTYL)BENZAMIDO]METHYL] 4 (BUTOXY)BENZYL]BUTANOIC ACID; 2 [4 METHOXY 3 [[4 (TRIFLUOROMETHYL)BENZAMIDO]METHYL]BENZYL]PENTANOIC ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PHENYLPROPIONIC ACID DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BINDING SITE; CRYSTAL STRUCTURE; CRYSTALLIZATION; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; ENANTIOMER; HYDROGEN BOND; HYDROPHOBICITY; LIGAND BINDING; PHYSICAL CHEMISTRY; PROTEIN CONFORMATION; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN PURIFICATION; PROTEIN STRUCTURE; STRUCTURE ANALYSIS; X RAY CRYSTALLOGRAPHY;

ADAMANTANE; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; HUMANS; HYDROPHOBIC AND HYDROPHILIC INTERACTIONS; LIGANDS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PHENYLPROPIONATES; PPAR ALPHA; PPAR DELTA; PPAR GAMMA; PROTEIN CONFORMATION; RECOMBINANT PROTEINS;

EID: 84863393296     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm2014293     Document Type: Article

References (29)

1. Chawla, A.; Repa, J. J.; Evans, R. M.; Mangelsdorf, D. J. Nuclear receptors and lipid physiology: Opening the X-files Science 2001, 294, 1866-1870 (Pubitemid 33101573)
2. Lemberger, T.; Desvergne, B.; Wahli, W. Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology Annu. Rev. Cell Dev. Biol. 1996, 12, 335-363 (Pubitemid 26422717)
3. Banner, C. D.; Göttlicher, M.; Widmark, E.; Sjövall, J.; Rafter, J. J.; Gustafsson, J. A Systematic analytical chemistry/cell assay approach to isolate activators of orphan nuclear receptors from biological extracts: characterization of peroxisome proliferator-activated receptor activators in plasma J. Lipid Res. 1993, 34, 1583-1591 (Pubitemid 23264331)
4. Schoonjans, K.; Martin, G.; Staels, B.; Auwerx, J. Peroxisome proliferator-activated receptors, orphans with ligands and functions Curr. Opin. Lipidol. 1997, 8, 159-166 (Pubitemid 27290462)
5. Mendez, M.; LaPointe, M. C. PPARgamma inhibition of cyclooxygenase-2, PGE2 synthase, and inducible nitric oxide synthase in cardiac myocytes Hypertension 2003, 42, 844-850 (Pubitemid 37237334)
6. Morrison, R. F.; Farmer, S. R. Role of PPARgamma in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18(INK4c) and p21(Waf1/Cip1), during adipogenesis J. Biol. Chem. 1999, 274, 17088-17097
7. Huang, J. W.; Shiau, C. W.; Yang, J.; Wang, D. S.; Chiu, H. C.; Chen, C. Y.; Chen, C. S. Development of small-molecule cyclin D1-ablative agents J. Med. Chem. 2006, 49, 4684-4689 (Pubitemid 44162695)
8. Wang, N.; Yin, R.; Liu, Y.; Mao, G.; Xi, F. Role of peroxisome proliferator-activated receptor-γ in atherosclerosis: an update Circ. J. 2011, 75, 528-535
9. Kaundal, R. K.; Sharma, S. S. Peroxisome proliferator-activated receptor gamma agonists as neuroprotective agents Drug News Perspect. 2010, 23, 241-256
10. Landreth, G. Therapeutic use of agonists of the nuclear receptor PPARgamma in Alzheimer's disease Curr. Alzheimer Res. 2007, 4, 159-164 (Pubitemid 46557505)
11. 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.; Willson, T. M.; Stimmel, J. B. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha Nature (London) 2002, 415, 813-817 (Pubitemid 34150506)
12. Cronet, P.; Petersen, J. F.; Folmer, R.; Blomberg, N.; Sjoblom, 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, 699-706 (Pubitemid 32772892)
13. 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 proliferator-activated receptor ligands on corepressor affinity Biochemistry 2003, 42, 9278-9287 (Pubitemid 36959235)
14. Ostberg, T.; Svensson, S.; Selén, G.; Uppenberg, J.; Thor, M.; Sundbom, M.; Sydow-Bäckman, M.; Gustavsson, A. L.; Jendeberg, L. A new class of peroxisome proliferator-activated receptor agonists with a novel binding epitope shows antidiabetic effects J. Biol. Chem. 2004, 279, 41124-30 (Pubitemid 39287714)
15. Ambrosio, A. L.; Dias, S. M.; Polikarpov, I.; Zurier, R. B.; Burstein, S. H.; Garratt, R. C. Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator- activated receptor gamma J. Biol. Chem. 2007, 282, 18625-18633 (Pubitemid 47100214)
16. Ban, S.; Kasuga, J.; Nakagome, I.; Nobusada, H.; Takayama, F.; Hirono, S.; Kawasaki, H.; Hashimoto, Y.; Miyachi, H. Structure-based design, synthesis, and nonalcoholic steatohepatitis (NASH)-preventive effect of phenylpropanoic acid peroxisome proliferator-activated receptor (PPAR) α-selective agonists Bioorg. Med. Chem. 2011, 19, 3183-3191
17. 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 α-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 (Pubitemid 44755267)
18. 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 (Pubitemid 46887670)
19. 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, 1110-1105
20. Ohashi, M.; Oyama, T.; Nakagome, I.; Sato, M.; Nishio, Y.; Nobusada, H.; Hirono, S.; Morikawa, K.; Hashimoto, Y.; Miyachi, H. Design, synthesis, and structural analysis of phenylpropanoic acid-type PPARγ-selective agonists: Discovery of reversed stereochemistry-activity relationship J. Med. Chem. 2011, 54, 331-341
21. 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
22. Kasuga, J.; Oyama, T.; Hirakawa, Y.; Makishima, M.; Morikawa, K.; Hashimoto, Y.; Miyachi, H. Improvement of the transactivation activity of phenylpropanoic acid-type peroxisome proliferator-activated receptor pan agonists: effect of introduction of fluorine at the linker part Bioorg. Med. Chem. Lett. 2008, 18, 4525-4528
23. 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
24. 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 & NMR system: A new software suite for macromolecular structure determination Acta Crystallogr. 1998, D54, 905-921
25. Jones, T. A.; Zou, J.-Y.; Cowan, S. W.; Kjeldgaard, M. Improved methods for building protein models in electron density maps and the location of errors in these models Acta Crystallogr. 1991, A47, 110-119
26. Kleywegt, G. J. Crystallographic refinement of ligand complexes Acta Crystallogr. 2007, D63, 94-100 (Pubitemid 46141484)
27. Fetrow, J. S. Omega loops: nonregular secondary structures significant in protein function and stability FASEB J. 1995, 9, 708-717
28. Xu, H, E.; Lambert, M. H.; Montana, V. G.; Parks, D. J.; Blanchard, 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 (Pubitemid 29290680)
29. Computer-graphic work and hydrogen bonding distances measurement were performed using MOE (Molecular Operating Environment) (Ryoka Systems Inc.).