LY518674: Potent and Selective PPAR-Alpha Agonist
Peroxisome proliferator-activated receptor (PPAR)-alpha agonists have been in development for the treatment of atherosclerosis since they demonstrated promise in animal models of dyslipidemia. It was believed that highly potent and selective PPAR-alpha agonists could improve upon fibrates, such as gemfibrozil and fenofibrate, which also act through modulation of PPAR-alpha, although weakly. However, the first PPAR-alpha agonist to reach phase 2 studies, the compound LY518674, under development with Eli Lilly (Indianapolis, Indiana), has shown mixed results, and it appears unlikely that this class of drugs will be widely developed further.
In 2 phase 2 studies, LY518674 did not show any advantages over fenofibrate in its effects on triglycerides and HDL cholesterol, and it actually raised levels of low-density lipoprotein (LDL) cholesterol and serum creatinine. The results of the 2 studies, both funded by Eli Lilly, were presented at the 2007 ACC meeting by Steven E. Nissen, MD (Cleveland Clinic, Cleveland, Ohio), and published simultaneously in JAMA.
The studies were designed to evaluate the safety and efficacy of LY518674 in one population with atherogenic dyslipidemia, with elevated triglycerides and low levels of HDL cholesterol, and in another population with hypercholesterolemia, with elevated levels of LDL cholesterol.
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