PMID- 19116277
OWN - NLM
STAT- MEDLINE
DCOM- 20090213
LR  - 20211020
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 106
IP  - 1
DP  - 2009 Jan 6
TI  - Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent.
PG  - 262-7
LID - 10.1073/pnas.0811325106 [doi]
AB  - 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).
FAU - Artis, Dean R
AU  - Artis DR
AD  - Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA. drartis@plexxikon.com
FAU - Lin, Jack J
AU  - Lin JJ
FAU - Zhang, Chao
AU  - Zhang C
FAU - Wang, Weiru
AU  - Wang W
FAU - Mehra, Upasana
AU  - Mehra U
FAU - Perreault, Mylene
AU  - Perreault M
FAU - Erbe, David
AU  - Erbe D
FAU - Krupka, Heike I
AU  - Krupka HI
FAU - England, Bruce P
AU  - England BP
FAU - Arnold, James
AU  - Arnold J
FAU - Plotnikov, Alexander N
AU  - Plotnikov AN
FAU - Marimuthu, Adhirai
AU  - Marimuthu A
FAU - Nguyen, Hoa
AU  - Nguyen H
FAU - Will, Sarah
AU  - Will S
FAU - Signaevsky, Maxime
AU  - Signaevsky M
FAU - Kral, John
AU  - Kral J
FAU - Cantwell, John
AU  - Cantwell J
FAU - Settachatgull, Calvin
AU  - Settachatgull C
FAU - Yan, Douglas S
AU  - Yan DS
FAU - Fong, Daniel
AU  - Fong D
FAU - Oh, Angela
AU  - Oh A
FAU - Shi, Shenghua
AU  - Shi S
FAU - Womack, Patrick
AU  - Womack P
FAU - Powell, Benjamin
AU  - Powell B
FAU - Habets, Gaston
AU  - Habets G
FAU - West, Brian L
AU  - West BL
FAU - Zhang, Kam Y J
AU  - Zhang KY
FAU - Milburn, Michael V
AU  - Milburn MV
FAU - Vlasuk, George P
AU  - Vlasuk GP
FAU - Hirth, K Peter
AU  - Hirth KP
FAU - Nolop, Keith
AU  - Nolop K
FAU - Bollag, Gideon
AU  - Bollag G
FAU - Ibrahim, Prabha N
AU  - Ibrahim PN
FAU - Tobin, James F
AU  - Tobin JF
LA  - eng
SI  - PDB/3ET0
SI  - PDB/3ET1
SI  - PDB/3ET2
SI  - PDB/3ET3
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20081230
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Adiponectin)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (PPAR gamma)
RN  - 0 (Peroxisome Proliferator-Activated Receptors)
SB  - IM
MH  - Adipocytes/cytology
MH  - Adiponectin/genetics
MH  - Animals
MH  - Cell Differentiation/drug effects
MH  - Cell Line
MH  - Diabetes Mellitus, Experimental/drug therapy
MH  - Drug Discovery/*methods
MH  - Humans
MH  - Hypoglycemic Agents/pharmacology/*therapeutic use
MH  - Mice
MH  - Obesity/drug therapy
MH  - PPAR gamma/*agonists/genetics
MH  - Peroxisome Proliferator-Activated Receptors/*agonists/genetics
MH  - Rats
MH  - Transcriptional Activation/drug effects
PMC - PMC2629228
COIS- Conflict of interest statement: The Sponsor is a member of the Scientific 
      Advisory Board of Plexxikon, Inc. The authors are either employees of Plexxikon, 
      Inc. or Wyeth Research with the exception of M.S. and J.K.
EDAT- 2009/01/01 09:00
MHDA- 2009/02/14 09:00
PMCR- 2009/07/06
CRDT- 2009/01/01 09:00
PHST- 2009/01/01 09:00 [entrez]
PHST- 2009/01/01 09:00 [pubmed]
PHST- 2009/02/14 09:00 [medline]
PHST- 2009/07/06 00:00 [pmc-release]
AID - 0811325106 [pii]
AID - 6275 [pii]
AID - 10.1073/pnas.0811325106 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):262-7. doi: 10.1073/pnas.0811325106. 
      Epub 2008 Dec 30.