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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Doshi
Lalit S
LS
Department of Pharmacology, Piramal Life Sciences Limited, 1 Nirlon Complex, Goregaon (E), Mumbai - 400 063, India.
Brahma
Manoja Kumar
MK
Bahirat
Umakant A
UA
Dixit
Amol V
AV
Nemmani
Kumar V S
KV
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D055808:Drug Discovery / Q000379:methods / Q000639:trends*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D009928:Organ Specificity / Q000235:genetics / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D007004:Hypoglycemic Agents; D047495:PPAR gamma