| STUDY |
Recent combinatorial studies at author's Co. have focused on peroxisome proliferator-activated receptors (PPARs) and other ligand-activated transcription factors in the nuclear receptor protein superfamily. Authors made a 10,000-member carboxylic acid library of potential PPAR-targeted agents. The library was screened against PPARdelta and an active pool of compounds was deconvoluted to find an active agent, called GW8547. Optimization of that compound using structure-based analog synthesis led to the identification of GW501516 as a potent, selective PPARdelta agonist The compound is now a clinical candidate for treatment of cardiovascular problems associated with an "orphan disease" called metabolic syndrome X "The utilization of target-biased library design and solid-phase parallel array synthesis were critical in accelerating the discovery of GW501516 as a potent, selective PPARdelta agonist. The work "exemplifies the potential utility of combinatorial chemistry in accelerating drug discovery."
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