Design and synthesis of novel and potent amide linked PPARgamma/delta dual agonists.
A series of potent amide linked PPARgamma/delta dual agonists (1a) has been discovered through rational design. In the ZDF rat model of type 2 diabetes, compound (R)-3-[4-(3-{1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid (42) from this series has demonstrated glucose lowering efficacy comparable to the marketed PPARgamma agonist rosiglitazone with less weight gain.
Shi
Qing
Q
Eli Lilly and Company, Lilly Research Labs, Lilly Corporate Center, Indianapolis, IN 46285, USA. shi_qing@lilly.com
Canada
Emily J
EJ
Xu
Yanping
Y
Warshawsky
Alan M
AM
Etgen
Garret J
GJ
Broderick
Carol L
CL
Clutinger
Cathleen K
CK
Irwin
Lynnie A
LA
Laurila
Michael E
ME
Montrose-Rafizadeh
Chahrzad
C
Oldham
Brian A
BA
Wang
Minmin
M
Winneroski
Leonard L
LL
Xie
Chaoyu
C
York
Jeremy S
JS
Yumibe
Nathan P
NP
Zink
Richard W
RW
Mantlo
Nathan
N
D000577:Amides / Q000737:chemistry*; D000818:Animals; D020650:Combinatorial Chemistry Techniques; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D015195:Drug Design; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D047494:PPAR delta / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats
C526678:(R)-3-(4-(3-(1-((5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)amino)ethyl)-5-fluoro-phenoxy)-2-ethylphenyl)propionic acid; D000577:Amides; D007211:Indoles; D047494:PPAR delta; D047495:PPAR gamma