title: Co-crystal structure guided array synthesis of PPARgamma inverse agonists.
abstract: 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.
authors.affiliation: Drug Discovery, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Trump
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Cobb
authors.forename: Barry G
authors.initials: BG
authors.lastname: Shearer
authors.forename: Millard H
authors.initials: MH
authors.lastname: Lambert
authors.forename: Robert T
authors.initials: RT
authors.lastname: Nolte
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: Richard G
authors.initials: RG
authors.lastname: Buckholz
authors.forename: Sumin M
authors.initials: SM
authors.lastname: Zhao
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Leesnitzer
authors.forename: Marie A
authors.initials: MA
authors.lastname: Iannone
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Pearce
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Billin
authors.forename: William J
authors.initials: WJ
authors.lastname: Hoekstra
mesh_terms: 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
chemical_list: D008024:Ligands; D010080:Oxazoles; D047495:PPAR gamma; C422415:farglitazar; D014443:Tyrosine