Co-crystal structure guided array synthesis of PPARgamma inverse agonists.
PPARgamma-activating thiazolidinediones and carboxylic acids such as farglitazar exert their anti-diabetic effects in part in PPARgamma rich adipose. Both pro- and anti-adipogenic PPARgamma ligands promote glucose and lipid lowering in animal models of diabetes. Herein, we disclose representatives of an array of 160 farglitazar analogues with atypical inverse agonism of PPARgamma in mature adipocytes.
Trump
Ryan P
RP
Drug Discovery, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Cobb
Jeffrey E
JE
Shearer
Barry G
BG
Lambert
Millard H
MH
Nolte
Robert T
RT
Willson
Timothy M
TM
Buckholz
Richard G
RG
Zhao
Sumin M
SM
Leesnitzer
Lisa M
LM
Iannone
Marie A
MA
Pearce
Kenneth H
KH
Billin
Andrew N
AN
Hoekstra
William J
WJ
D003460:Crystallization; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D008024:Ligands; D010080:Oxazoles; D047495:PPAR gamma; C422415:farglitazar; D014443:Tyrosine