3KDT

Crystal structure of peroxisome proliferator-activatedeceptor alpha (PPARalpha) complex with N-3-((2-(4-Chlorophenyl)-5-methyl-1,3-oxazol-4-yl)methoxy)benzyl)-N-(methoxycarbonyl)glycine

Summary for 3KDT

• Entry DOI: 10.2210/pdb3kdt/pdb
• Related: 3KDU
• Descriptor: Peroxisome proliferator-activated receptor alpha, N-(3-{[2-(4-chlorophenyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)-N-(methoxycarbonyl)glycine (3 entities in total)
• Functional Keywords: nuclear hormone receptor, transcription regulation, activator, dna-binding, lipid-binding, receptor, transcription, hormone receptor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q07869
• Total number of polymer chains: 2
• Total formula weight: 63522.62

Authors

Muckelbauer, J.K. (deposition date: 2009-10-23, release date: 2010-04-28, Last modification date: 2024-02-21)

Primary citation

Li, J.,Kennedy, L.J.,Shi, Y.,Tao, S.,Ye, X.Y.,Chen, S.Y.,Wang, Y.,Hernandez, A.S.,Wang, W.,Devasthale, P.V.,Chen, S.,Lai, Z.,Zhang, H.,Wu, S.,Smirk, R.A.,Bolton, S.A.,Ryono, D.E.,Zhang, H.,Lim, N.K.,Chen, B.C.,Locke, K.T.,O'Malley, K.M.,Zhang, L.,Srivastava, R.A.,Miao, B.,Meyers, D.S.,Monshizadegan, H.,Search, D.,Grimm, D.,Zhang, R.,Harrity, T.,Kunselman, L.K.,Cap, M.,Kadiyala, P.,Hosagrahara, V.,Zhang, L.,Xu, C.,Li, Y.X.,Muckelbauer, J.K.,Chang, C.,An, Y.,Krystek, S.R.,Blanar, M.A.,Zahler, R.,Mukherjee, R.,Cheng, P.T.,Tino, J.A.
Discovery of an oxybenzylglycine based peroxisome proliferator activated receptor alpha selective agonist 2-((3-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic acid (BMS-687453).
J.Med.Chem., 53:2854-2864, 2010

PubMed Abstract: An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.

PubMed: 20218621
DOI: 10.1021/jm9016812

Experimental method

X-RAY DIFFRACTION (2.7 Å)