gw-590735 and Dyslipidemias

The identification of small molecule agonists for the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR-beta/delta, NR1C2) has enabled the characterization of this receptor's functions in preclinical models. Subsequently, a number of small molecule agonists of PPAR-beta/delta have been progressed into clinical trials.. This review will examine the major preclinical findings that underpin the hypothesis that PPAR-beta/delta agonists may be beneficial in treating dyslipidemia and Type 2 diabetes, as well as emerging clinical data with a variety of PPAR-beta/delta agonists.. The literature concerning preclinical experiments that combine in vivo and in vitro mechanistic studies are reviewed and compared with the results of the early clinical trials.. Thus far, the activities of the agonists seen in the clinic are broadly similar to those seen in preclinical models. However, it is still not known if PPAR-beta/delta agonists will truly be differentiated enough from current treatments to justify their use in treating dyslipidemia or Type 2 diabetes. Major challenges for the development of PPAR-beta/delta agonists exist and the path forward is as yet undefined.

Topics: Animals; Atherosclerosis; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dyslipidemias; Glucose; Humans; Insulin Resistance; Lipoproteins; PPAR delta; PPAR-beta; Propionates; Thiazoles

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.

Topics: Animals; Apolipoprotein A-I; Cholesterol, HDL; Cholesterol, VLDL; Crystallography, X-Ray; Dogs; Dyslipidemias; Humans; Ligands; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Molecular; PPAR alpha; Propionates; Protein Structure, Tertiary; Rats; Rats, Wistar; Structure-Activity Relationship; Thiazoles; Triglycerides