Discovery of a novel series of peroxisome proliferator-activated receptor alpha/gamma dual agonists for the treatment of type 2 diabetes and dyslipidemia.
A series of 2-aryloxy-2-methyl-propionic acid compounds and related analogues were designed, synthesized, and evaluated for their PPAR agonist activities. 2-[(5,7-Dipropyl-3-trifluoromethyl)-benzisoxazol-6-yloxy]-2-methylpropionic acid (4) was identified as a PPARalpha/gamma dual agonist with relative PPARalpha selectivity and demonstrated potent efficacy in lowering both glucose and lipids in animal models without causing body weight gain. The PPARalpha activity of 4 appeared to have played a significant role in lowering glucose levels in db/db mice.
Liu
Kun
K
Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. kun-liu@merck.com
Xu
Libo
L
Berger
Joel P
JP
Macnaul
Karen L
KL
Zhou
Gauchao
G
Doebber
Thomas W
TW
Forrest
Michael J
MJ
Moller
David E
DE
Jones
A Brian
AB
D041721:3T3-L1 Cells; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D019556:COS Cells; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004285:Dogs; D050556:Fatty Acid-Binding Proteins; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008820:Mice, Obese; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain
C500157:2-((5,7-dipropyl-3-trifluoromethyl)benzisoxazol-6-yloxy)-2-methylpropionic acid; D001786:Blood Glucose; D002352:Carrier Proteins; D050556:Fatty Acid-Binding Proteins; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007555:Isoxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D011422:Propionates; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol