3TY0

Structure of PPARgamma ligand binding domain in complex with (R)-5-(3-((3-(6-methoxybenzo[d]isoxazol-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-5-methyloxazolidine-2,4-dione

Summary for 3TY0

• Entry DOI: 10.2210/pdb3ty0/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, (5R)-5-(3-{[3-(6-methoxy-1,2-benzoxazol-3-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]methyl}phenyl)-5-methyl-1,3-oxazolidine-2,4-dione (3 entities in total)
• Functional Keywords: nuclear receptor ligand binding domain, transcription regulator
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P37231
• Total number of polymer chains: 2
• Total formula weight: 64156.22

Authors

Soisson, S.M.,Meinke, P.M.,McKeever, B.,Liu, W. (deposition date: 2011-09-23, release date: 2011-11-23, Last modification date: 2024-02-28)

Primary citation

Liu, W.,Lau, F.,Liu, K.,Wood, H.B.,Zhou, G.,Chen, Y.,Li, Y.,Akiyama, T.E.,Castriota, G.,Einstein, M.,Wang, C.,McCann, M.E.,Doebber, T.W.,Wu, M.,Chang, C.H.,McNamara, L.,McKeever, B.,Mosley, R.T.,Berger, J.P.,Meinke, P.T.
Benzimidazolones: a new class of selective peroxisome proliferator-activated receptor gamma (PPAR-gamma) modulators.
J.Med.Chem., 54:8541-8554, 2011

PubMed Abstract: A series of benzimidazolone carboxylic acids and oxazolidinediones were designed and synthesized in search of selective PPARγ modulators (SPPARγMs) as potential therapeutic agents for the treatment of type II diabetes mellitus (T2DM) with improved safety profiles relative to rosiglitazone and pioglitazone, the currently marketed PPARγ full agonist drugs. Structure-activity relationships of these potent and highly selective SPPARγMs were studied with a focus on their unique profiles as partial agonists or modulators. A variety of methods, such as X-ray crystallographic analysis, PPARγ transactivation coactivator profiling, gene expression profiling, and mutagenesis studies, were employed to reveal the differential interactions of these new analogues with PPARγ receptor in comparison to full agonists. In rodent models of T2DM, benzimidazolone analogues such as (5R)-5-(3-{[3-(5-methoxybenzisoxazol-3-yl)benzimidazol-1-yl]methyl}phenyl)-5-methyloxazolidinedione (51) demonstrated efficacy equivalent to that of rosiglitazone. Side effects, such as fluid retention and heart weight gain associated with PPARγ full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models.

PubMed: 22070604
DOI: 10.1021/jm201061j

Experimental method

X-RAY DIFFRACTION (2 Å)