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

3TY0 の概要

• エントリーDOI: 10.2210/pdb3ty0/pdb
• 分子名称: 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)
• 機能のキーワード: nuclear receptor ligand binding domain, transcription regulator
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: P37231
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64156.22

構造登録者

Soisson, S.M.,Meinke, P.M.,McKeever, B.,Liu, W. (登録日: 2011-09-23, 公開日: 2011-11-23, 最終更新日: 2024-02-28)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2 Å)