1zeo

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Revision as of 18:27, 12 November 2007

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spinqualitylabelsall models 1zeo, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal Structure of Human PPAR-gamma Ligand Binding Domain Complexed with an Alpha-Aryloxyphenylacetic Acid Agonist

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The synthesis and structure-activity relationships of novel series of, alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are, reported. The initial search for surrogates of the ester group in the, screen lead led first to the optimization of a subseries with a ketone, moiety. Further efforts to modify the ketone subseries led to the design, and synthesis of two new subseries containing fused heterocyclic ring, systems. All these analogues were characterized by their "super" PPARalpha, agonist activity and weak or partial agonist activity on PPARgamma in, PPAR-GAL4 transactivation assays despite their similar binding affinities, for both receptors. The cocrystal structures of compounds 7 and, rosiglitazone with PPARgamma-LBD were compared, and significant, differences were found in their interactions with the receptor. Select, analogues in each subseries were further evaluated for in vivo efficacy., They all showed excellent anti-hyperglycemic efficacy in a db/db mouse, model and hypolipidemic activity in hamster and dog models without, provoking the typical PPARgamma-associated side effects in the rat, tolerability assay.

Disease

Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[601487], Diabetes mellitus, insulin-resistant, with acanthosis nigricans and hypertension OMIM:[601487], Glioblastoma, susceptibility to OMIM:[601487], Insulin resistance, severe, digenic OMIM:[601487], Lipodystrophy, familial partial OMIM:[601487], Obesity, resistance to OMIM:[601487], Obesity, severe OMIM:[601487]

About this Structure

1ZEO is a Single protein structure of sequence from Homo sapiens with C01 as ligand. Full crystallographic information is available from OCA.

Reference

Design and synthesis of alpha-aryloxyphenylacetic acid derivatives: a novel class of PPARalpha/gamma dual agonists with potent antihyperglycemic and lipid modulating activity., Shi GQ, Dropinski JF, McKeever BM, Xu S, Becker JW, Berger JP, MacNaul KL, Elbrecht A, Zhou G, Doebber TW, Wang P, Chao YS, Forrest M, Heck JV, Moller DE, Jones AB, J Med Chem. 2005 Jun 30;48(13):4457-68. PMID:15974597

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