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

The peroxisome proliferator activated receptors PPAR alpha, PPAR gamma, and PPAR delta 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 PPAR alpha 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 PPAR alpha agonists. Modification of the selective PPAR delta 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 PPAR alpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPAR alpha and at least 500-fold selectivity versus PPAR delta and PPAR gamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.