Potent and Highly Selective Benzimidazole Inhibitors of PI3-Kinase Delta

被引：60

作者：

Murray, Jeremy M. ^{[1
]}

Sweeney, Zachary K. ^{[1
]}

Chan, Bryan K. ^{[1
]}

Balazs, Mercedesz ^{[1
]}

Bradley, Erin ^{[1
]}

Castanedo, Georgette ^{[1
]}

Chabot, Christine ^{[1
]}

Chantry, David ^{[1
]}

Flagella, Michael ^{[1
]}

Goldstein, David M. ^{[3
]}

Kondru, Rama ^{[3
]}

Lesnick, John ^{[1
]}

Li, Jun ^{[1
]}

Lucas, Matthew C. ^{[3
]}

Nonomiya, Jim ^{[1
]}

Pang, Jodie ^{[1
]}

Price, Stephen ^{[2
]}

Salphati, Laurent ^{[1
]}

Safina, Brian ^{[1
]}

Savy, Pascal P. A. ^{[2
]}

Seward, Eileen M. ^{[2
]}

Ultsch, Mark ^{[1
]}

Sutherlin, Daniel P. ^{[1
]}

机构：

[1] Genentech Inc, San Francisco, CA 94080 USA

[2] Argenta Discovery, Harlow CM19 5TR, Essex, England

[3] Roche Res Ctr, Nutley, NJ 07110 USA

来源：

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

关键词：

PHOSPHOINOSITIDE; 3-KINASE; RHEUMATOID-ARTHRITIS; B-CELL; DISCOVERY; CANCER; IDENTIFICATION; GDC-0941; THERAPY; KINASE; DRUGS;

D O I：

10.1021/jm300717c

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Inhibition of PI3K delta is considered to be an attractive mechanism for the treatment of inflammatory diseases and leukocyte malignancies. Using a structure-based design approach, we have identified a series of potent and selective benzimidazole-based inhibitors of PI3K delta. These inhibitors do not occupy the selectivity pocket between Trp760 and Met752 that is induced by other families of PI3K delta inhibitors. Instead, the selectivity of the compounds for inhibition of PI3K delta relative to other PI3K isoforms appears to be due primarily to the strong interactions these inhibitors are able to make with Trp760 in the PI3K delta binding pocket. The pharmacokinetic properties and the ability of compound 5 to inhibit the function of B-cells in vivo are described.

引用

页码：7686 / 7695

页数：10

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