2. Academic Validation
  3. Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents

Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents

  • J Med Chem. 2007 Feb 22;50(4):685-95. doi: 10.1021/jm058056x.
Michael L Sierra 1,  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
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Laboratoire GlaxoSmithKline, Centre de Recherches, 25-27 avenue du Québec, 91951 Les Ulis, France, USA.
PMID: 17243659 DOI: 10.1021/jm058056x
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.

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