| Literature DB >> 17243659 |
Michael L Sierra1, Véronique Beneton, Anne-Bénédict Boullay, Thierry Boyer, Andrew G Brewster, Frédéric Donche, Marie-Claire Forest, Marie-Hélène Fouchet, Françoise J Gellibert, Didier A Grillot, Millard H Lambert, Alain Laroze, Christelle Le Grumelec, Jean Michel Linget, Valerie G Montana, Van-Loc Nguyen, Edwige Nicodème, Vipul Patel, Annie Penfornis, Olivier Pineau, Danig Pohin, Florent Potvain, Géraldine Poulain, Cécile Bertho Ruault, Michael Saunders, Jérôme Toum, H Eric Xu, Robert X Xu, Pascal M Pianetti.
Abstract
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.Entities:
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Year: 2007 PMID： 17243659 DOI： 10.1021/jm058056x
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446