2p54

From Proteopedia

a crystal structure of PPAR alpha bound with SRC1 peptide and GW735

Overview

The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and, PPARdelta are ligand-activated transcription factors that play a key role, in lipid homeostasis. The fibrates raise circulating levels of, high-density lipoprotein cholesterol and lower levels of triglycerides in, part through their activity as PPARalpha agonists; however, the low, potency and restricted selectivity of the fibrates may limit their, efficacy, and it would be desirable to develop more potent and selective, PPARalpha agonists. Modification of the selective PPARdelta agonist 1, (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of, the fibrates led to a marked shift in potency and selectivity toward, PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 =, 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and, PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials, for the treatment of diseases of lipid imbalance.

Disease

Known diseases associated with this structure: Hyperapobetalipoproteinemia, susceptibility to OMIM:[170998]

About this Structure

2P54 is a Protein complex structure of sequences from Homo sapiens with 735 as ligand. Active as Histone acetyltransferase, with EC number 2.3.1.48 Full crystallographic information is available from OCA.

Reference

Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents., Sierra ML, Beneton V, Boullay AB, Boyer T, Brewster AG, Donche F, Forest MC, Fouchet MH, Gellibert FJ, Grillot DA, Lambert MH, Laroze A, Le Grumelec C, Linget JM, Montana VG, Nguyen VL, Nicodeme E, Patel V, Penfornis A, Pineau O, Pohin D, Potvain F, Poulain G, Ruault CB, Saunders M, Toum J, Xu HE, Xu RX, Pianetti PM, J Med Chem. 2007 Feb 22;50(4):685-95. Epub 2007 Jan 23. PMID:17243659

Page seeded by OCA on Mon Nov 12 23:20:41 2007