Today's challenges and tomorrow's opportunities: ligands to peroxisome proliferator‐activated receptors as therapies for type 2 diabetes and the metabolic syndrome

Abstract

AbstractFor over a decade, scientists have been investigating the sub‐family of nuclear hormone receptors known as the peroxisome proliferator‐activated receptors (PPARs) as potential targets for improved therapies for type 2 diabetes (T2D). Initial efforts focused on compounds with the thiazolidinedione (TZD) structure, synthesizing compounds based on structural differences followed by testing in rodent models without knowing the molecular target. Once the receptor for the TZDs was identified as PPARγ, more extensive efforts began to identify and develop improved versions of the TZDs. Many biotechnology and pharmaceutical companies using this information established assays that were used in high through‐put screening efforts to identify compounds with greater affinity and selectivity to the receptor. Surprising, these extensive efforts have not led to improved therapies but, in fact, have identified molecules with improved efficacy but with more severe and diverse liabilities. Today, scientists continue to pursue the PPAR subfamily as a target for advanced treatments for T2D and the metabolic syndrome. New approaches include selective PPAR modulators, expansion into the PPARα and PPARδ subtypes, and partial agonists with dual or pan PPAR properties. These drug discovery efforts will continue, as T2D and the associated metabolic diseases become severe medical problems in nations worldwide. Eventually, new and improved therapies will emerge based on the extensive preclinical and clinical knowledge that has accumulated from research and discovery on PPARs by dedicated and thoughtful scientists in search of improved therapies for people with T2D. Drug Dev. Res. 67:574–578, 2006. © 2006 Wiley‐Liss, Inc.