Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent.
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).
Artis
Dean R
DR
Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA. drartis@plexxikon.com
Lin
Jack J
JJ
Zhang
Chao
C
Wang
Weiru
W
Mehra
Upasana
U
Perreault
Mylene
M
Erbe
David
D
Krupka
Heike I
HI
England
Bruce P
BP
Arnold
James
J
Plotnikov
Alexander N
AN
Marimuthu
Adhirai
A
Nguyen
Hoa
H
Will
Sarah
S
Signaevsky
Maxime
M
Kral
John
J
Cantwell
John
J
Settachatgull
Calvin
C
Yan
Douglas S
DS
Fong
Daniel
D
Oh
Angela
A
Shi
Shenghua
S
Womack
Patrick
P
Powell
Benjamin
B
Habets
Gaston
G
West
Brian L
BL
Zhang
Kam Y J
KY
Milburn
Michael V
MV
Vlasuk
George P
GP
Hirth
K Peter
KP
Nolop
Keith
K
Bollag
Gideon
G
Ibrahim
Prabha N
PN
Tobin
James F
JF
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
D052242:Adiponectin; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors