Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent

Dean R. Artis, Jack J. Lin, Chao Zhang, Weiru Wang, Upasana Mehra, Mylene Perreault, David Erbe, Heike I. Krupka, Bruce P. England, James Arnold, Alexander N. Plotnikov, Adhirai Marimuthu, Hoa Nguyen, Sarah Will, Maxime Signaevsky, John Kral, John Cantwell, Calvin Settachatgull, Douglas S. Yan, Daniel FongAngela Oh, Shenghua Shi, Patrick Womack, Benjamin Powell, Gaston Habets, Brian L. West, Kam Y.J. Zhang, Michael V. Milburn, George P. Vlasuk, K. Peter Hirth, Keith Nolop, Gideon Bollag, Prabha N. Ibrahim, James F. Tobin

Research output: Contribution to journalArticlepeer-review

110 Scopus citations

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), PPARα, PPARγ, and PPARδ. Transcriptional transactivation assays were used to select compounds from this chemical series with a bias toward partial agonism toward PPARγ, to circumvent the clinically observed side effects of full PPARγ 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 PPARγ. Compared with full PPARγ-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).

Original languageEnglish
Pages (from-to)262-267
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number1
DOIs
StatePublished - 6 Jan 2009
Externally publishedYes

Keywords

  • Adiponectin
  • Diabetes
  • PPAR pan-agonist
  • Partial agonist
  • Scaffold-based drug discovery

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