title: Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent.
abstract: In a search for more effective anti-diabetic treatment, we used a process coupling low-affinity biochemical screening with high-throughput co-crystallography in the design of a series of compounds that selectively modulate the activities of all three peroxisome proliferator-activated receptors (PPARs), PPARalpha, PPARgamma, and PPARdelta. Transcriptional transactivation assays were used to select compounds from this chemical series with a bias toward partial agonism toward PPARgamma, to circumvent the clinically observed side effects of full PPARgamma agonists. Co-crystallographic characterization of the lead molecule, indeglitazar, in complex with each of the 3 PPARs revealed the structural basis for its PPAR pan-activity and its partial agonistic response toward PPARgamma. Compared with full PPARgamma-agonists, indeglitazar is less potent in promoting adipocyte differentiation and only partially effective in stimulating adiponectin gene expression. Evaluation of the compound in vivo confirmed the reduced adiponectin response in animal models of obesity and diabetes while revealing strong beneficial effects on glucose, triglycerides, cholesterol, body weight, and other metabolic parameters. Indeglitazar has now progressed to Phase II clinical evaluations for Type 2 diabetes mellitus (T2DM).
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA. drartis@plexxikon.com
authors.forename: Dean R
authors.initials: DR
authors.lastname: Artis
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Lin
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Upasana
authors.initials: U
authors.lastname: Mehra
authors.forename: Mylene
authors.initials: M
authors.lastname: Perreault
authors.forename: David
authors.initials: D
authors.lastname: Erbe
authors.forename: Heike I
authors.initials: HI
authors.lastname: Krupka
authors.forename: Bruce P
authors.initials: BP
authors.lastname: England
authors.forename: James
authors.initials: J
authors.lastname: Arnold
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Plotnikov
authors.forename: Adhirai
authors.initials: A
authors.lastname: Marimuthu
authors.forename: Hoa
authors.initials: H
authors.lastname: Nguyen
authors.forename: Sarah
authors.initials: S
authors.lastname: Will
authors.forename: Maxime
authors.initials: M
authors.lastname: Signaevsky
authors.forename: John
authors.initials: J
authors.lastname: Kral
authors.forename: John
authors.initials: J
authors.lastname: Cantwell
authors.forename: Calvin
authors.initials: C
authors.lastname: Settachatgull
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Yan
authors.forename: Daniel
authors.initials: D
authors.lastname: Fong
authors.forename: Angela
authors.initials: A
authors.lastname: Oh
authors.forename: Shenghua
authors.initials: S
authors.lastname: Shi
authors.forename: Patrick
authors.initials: P
authors.lastname: Womack
authors.forename: Benjamin
authors.initials: B
authors.lastname: Powell
authors.forename: Gaston
authors.initials: G
authors.lastname: Habets
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.forename: Kam Y J
authors.initials: KY
authors.lastname: Zhang
authors.forename: Michael V
authors.initials: MV
authors.lastname: Milburn
authors.forename: George P
authors.initials: GP
authors.lastname: Vlasuk
authors.forename: K Peter
authors.initials: KP
authors.lastname: Hirth
authors.forename: Keith
authors.initials: K
authors.lastname: Nolop
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
authors.forename: Prabha N
authors.initials: PN
authors.lastname: Ibrahim
authors.forename: James F
authors.initials: JF
authors.lastname: Tobin
mesh_terms: D017667:Adipocytes / Q000166:cytology; D052242:Adiponectin / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009765:Obesity / Q000188:drug therapy; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000235:genetics; D051381:Rats; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D052242:Adiponectin; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors