2,5-Diaminopyrimidines and 3,5-disubstituted azapurines as inhibitors of glycogen synthase kinase-3 (GSK-3)

被引：20

作者：

Lum, Christopher ^{[1
]}

Kahl, Jeff ^{[2
]}

Kessler, Linda ^{[3
]}

Kucharski, Jeff ^{[3
]}

Lundstrom, Jan ^{[1
]}

Miller, Stephen ^{[4
]}

Nakanishi, Hiroshi ^{[5
]}

Pei, Yazhong ^{[6
]}

Pryor, Kent ^{[1
]}

Roberts, Edward ^{[7
]}

Sebo, Lubomir ^{[8
]}

Sullivan, Robert ^{[9
]}

Urban, Jan ^{[10
]}

Wang, Zhijun ^{[6
]}

机构：

[1] Kemia Inc, San Diego, CA 92121 USA

[2] Azaya Therapeut, San Antonio, TX 78249 USA

[3] Intellikine, La Jolla, CA 92037 USA

[4] Array Biopharma, Boulder, CO 80301 USA

[5] Univ So Calif, Ctr Stem Cell & Regenerat Med, Keck Sch Med, Los Angeles, CA 90033 USA

[6] CalciMed, La Jolla, CA 92037 USA

[7] Scripps Res Inst, La Jolla, CA 92037 USA

[8] Pacific Biosci, Menlo Pk, CA 94025 USA

[9] Amylin Pharmaceut Inc, San Diego, CA 92121 USA

[10] Nanosyn, San Diego, CA 92121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 12期

关键词：

kinase inhibitors; GSK-3; aurora A; diabetes; Alzheimer's; depression; bipolar disorder; molecular modeling;

D O I：

10.1016/j.bmcl.2008.05.001

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of two classes of pyrimidine-based inhibitors of GSK-3 is described. Optimization of these series led to inhibitors with IC(50) < 10 nM and > 100-fold selectivity over Aurora A kinase. A proposed binding mode of 21b is presented. One compound (33) of the pyrimidine series showed promising pharmacokinetic parameters. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：3578 / 3581

页数：4

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