2. Academic Validation
  3. Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent

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

  • Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):262-7. doi: 10.1073/pnas.0811325106.
Dean R Artis 1,  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 Fong,  Angela 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
Affiliations

Affiliation

  • 1 Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA. drartis@plexxikon.com
PMID: 19116277 DOI: 10.1073/pnas.0811325106
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).

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