Discovery and development of selective PPAR gamma modulators as safe and effective antidiabetic agents.

IMPORTANCE OF THE FIELD: PPARgamma full agonists (pioglitazone and rosiglitazone) are the mainstay drugs for the treatment of type 2 diabetes; however, mechanism-based side effects have limited their full therapeutic potential. In recent years, much progress has been achieved in the discovery and development of selective PPARgamma modulators (SPPARgammaMs) as safer alternatives to PPARgamma full agonists. AREAS COVERED IN THIS REVIEW: This review focuses on the preclinical and clinical data of all the SPPARgammaMs discovered so far, retrieved by searching PubMed, Prous Integrity database and company news updates from 1999 to date. WHAT THE READER WILL GAIN: Here we thoroughly discuss SPPARgammaMs' mode of action, briefly examine new ways to identify superior SPPARgammaMs, and finally, compare and contrast the pharmacological and safety profile of various agents. TAKE HOME MESSAGE: The preclinical and clinical findings clearly suggest that selective PPARgamma modulators have the potential to become the next generation of PPARgamma agonists: effective insulin sensitizers with a superior safety profile to that of PPARgamma full agonists.