Discovery and in Vivo Evaluation of Dual PI3Kβ/δ Inhibitors

被引：42

作者：

de Turiso, Felix Gonzalez-Lopez ^{[1
]}

Shin, Youngsook ^{[1
]}

Brown, Matthew ^{[1
]}

Cardozo, Mario ^{[1
]}

Chen, Yi ^{[1
]}

Fong, David ^{[3
]}

Hao, Xiaolin ^{[1
]}

He, Xiao ^{[1
]}

Henne, Kirk ^{[2
]}

Hu, Yi-Ling ^{[3
]}

Johnson, Michael G. ^{[1
]}

Kohn, Todd ^{[1
]}

Lohman, Julia ^{[1
]}

McBride, Helen J. ^{[3
]}

McGee, Lawrence R. ^{[1
]}

Medina, Julio C. ^{[1
]}

Metz, Daniela ^{[3
]}

Miner, Kent ^{[3
]}

Mohn, Deanna ^{[3
]}

Pattaropong, Vatee ^{[1
]}

Seganish, Jennifer ^{[1
]}

Simard, Jillian L. ^{[1
]}

Wannberg, Sharon ^{[3
]}

Whittington, Douglas A. ^{[4
]}

Yu, Gang ^{[3
]}

Cushing, Timothy D. ^{[1
]}

机构：

[1] Amgen Inc, Dept Therapeut Discovery, San Francisco, CA 94080 USA

[2] Amgen Inc, Dept Pharmacokinet & Drug Metab, San Francisco, CA 94080 USA

[3] Amgen Inc, Dept Inflammat Res, Thousand Oaks, CA 91320 USA

[4] Amgen Inc, Dept Therapeut Discovery, Cambridge, MA 02142 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 17期

关键词：

PHOSPHOINOSITIDE; 3-KINASE; RHEUMATOID-ARTHRITIS; PI3K/AKT PATHWAY; DRUG DISCOVERY; ACTIVATION; CANCER; INFLAMMATION; METABOLISM; P110-DELTA; PI3K-DELTA;

D O I：

10.1021/jm300679u

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3K beta/delta dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3K beta and delta isoforms in the treatment of a number of inflammatory diseases.

引用

页码：7667 / 7685

页数：19

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