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

被引：113

作者：

Artis, Dean R. ^{[1
]}

Lin, Jack J. ^{[1
]}

Zhang, Chao ^{[1
]}

Wang, Weiru ^{[1
]}

Mehra, Upasana ^{[1
]}

Perreault, Mylene ^{[2
]}

Erbe, David ^{[2
]}

Krupka, Heike I. ^{[1
]}

England, Bruce P. ^{[1
]}

Arnold, James ^{[1
]}

Plotnikov, Alexander N. ^{[1
]}

Marimuthu, Adhirai ^{[1
]}

Nguyen, Hoa ^{[1
]}

Will, Sarah ^{[2
]}

Signaevsky, Maxime ^{[3
]}

Kral, John ^{[3
]}

Cantwell, John ^{[1
]}

Settachatgull, Calvin ^{[1
]}

Yan, Douglas S. ^{[1
]}

Fong, Daniel ^{[1
]}

Oh, Angela ^{[1
]}

Shi, Shenghua ^{[1
]}

Womack, Patrick ^{[1
]}

Powell, Benjamin ^{[1
]}

Habets, Gaston ^{[1
]}

West, Brian L. ^{[1
]}

Zhang, Kam Y. J. ^{[1
]}

Milburn, Michael V. ^{[1
]}

Vlasuk, George P. ^{[2
]}

Hirth, K. Peter ^{[1
]}

Nolop, Keith ^{[1
]}

Bollag, Gideon ^{[1
]}

Ibrahim, Prabha N. ^{[1
]}

Tobin, James F. ^{[2
]}

机构：

[1] Plexxikon Inc, Berkeley, CA 94710 USA

[2] Wyeth Ayerst Res, Dept Cardiovasc & Metab Dis, Cambridge, MA 02140 USA

[3] Suny Downstate Med Ctr, Dept Surg, Brooklyn, NY 11203 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 01期

关键词：

adiponectin; diabetes; partial agonist; PPAR pan-agonist; Scaffold-based drug discovery; INSULIN SENSITIVITY; RECEPTOR-GAMMA; ALPHA/GAMMA AGONIST; METABOLIC PROFILE; LIGAND-BINDING; DRUG DISCOVERY; ADIPONECTIN; RATS; CELL; ROSIGLITAZONE;

D O I：

10.1073/pnas.0811325106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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

引用

页码：262 / 267

页数：6

共 30 条

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