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.
Subject(s)
Cholesterol, HDL/blood , PPAR alpha/agonists , Propionates/chemical synthesis , Thiazoles/chemical synthesis , Animals , Apolipoprotein A-I/genetics , Cholesterol, VLDL/blood , Crystallography, X-Ray , Dogs , Dyslipidemias/blood , Dyslipidemias/drug therapy , Humans , Ligands , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Molecular , PPAR alpha/chemistry , Propionates/pharmacokinetics , Propionates/pharmacology , Protein Structure, Tertiary , Rats , Rats, Wistar , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Triglycerides/bloodABSTRACT
We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor delta (PPARdelta). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to 7k (GW501516) and 7l (GW0742), which shows an EC(50) of 1.1 nM against PPARdelta with 1000-fold selectivity over the other human subtypes.
