PPAR-beta/delta agonists for Type 2 diabetes and dyslipidemia: an adopted orphan still looking for a home.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Billin
Andrew N
AN
GlaxoSmithKline, Inc., 5 Moore Drive, Research Triangle Park, NC 27709, USA. andrew.n.billin@gsk.com
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D050171:Dyslipidemias / Q000188:drug therapy*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D008074:Lipoproteins / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists*; D048068:PPAR-beta / Q000819:agonists*; D011422:Propionates / Q000009:adverse effects / Q000627:therapeutic use; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use
C518308:2-methyl-2-(4-(((4-methyl-2-(4-trifluoromethylphenyl)-thiazol-5-ylcarbonyl)amino)methyl)phenoxy)propionic acid; C425931:GW 501516; D008074:Lipoproteins; D047494:PPAR delta; D048068:PPAR-beta; D011422:Propionates; D013844:Thiazoles; D005947:Glucose