Discovery of a peroxisome proliferator activated receptor gamma (PPARgamma) modulator with balanced PPARalpha activity for the treatment of type 2 diabetes and dyslipidemia.
A series of 3-acylindole-1-benzylcarboxylic acids were designed and synthesized while searching for a PPARgamma modulator with additional moderate intrinsic PPARalpha agonistic activity. 2-[3-[[3-(4-Chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy]-(2R)-butanoic acid (12d) was identified as such an agent which demonstrated potent efficacy in lowering both glucose and lipids in multiple animal models with significantly attenuated side effects such as fluid retention and heart weight gain associated with PPARgamma full agonists. The moderate PPARalpha activity of 12d not only contributed to the agent's ability to manage lipid profiles but also appears to have potentiated its PPARgamma efficacy in lowering glucose levels in preclinical diabetic animal models.
Liu
Weiguo
W
Merck Research Laboratories, Rahway, New Jersey 07065, USA. weiguo_liu@merck.com
Liu
Kun
K
Wood
Harold B
HB
McCann
Margaret E
ME
Doebber
Thomas W
TW
Chang
Ching H
CH
Akiyama
Taro E
TE
Einstein
Monica
M
Berger
Joel P
JP
Meinke
Peter T
PT
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D020148:Butyric Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004285:Dogs; D055808:Drug Discovery; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship
D001786:Blood Glucose; D007211:Indoles; D047495:PPAR gamma; D020148:Butyric Acid; D002784:Cholesterol