SAR studies around a series of triazolopyridines as potent and selective PI3Kγ inhibitors

被引：40

作者：

Bell, Kathryn ^{[1
]}

Sunose, Mihiro ^{[1
]}

Ellard, Katie ^{[1
]}

Cansfield, Andrew ^{[1
]}

Taylor, Jess ^{[1
]}

Miller, Warren ^{[1
]}

Ramsden, Nigel ^{[1
]}

Bergamini, Giovanna ^{[2
]}

Neubauer, Gitte ^{[2
]}

机构：

[1] Cellzome Ltd, Saffron Walden CB10 1XL, Essex, England

[2] Cellzome AG, D-69117 Heidelberg, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 16期

关键词：

PI3K gamma; Kinase inhibitor; Inflammation; Triazolopyridine; Collagen induced arthritis; SMALL-MOLECULE INHIBITORS; PHOSPHOINOSITIDE; 3-KINASE; EMBRYONIC LETHALITY; P110-ALPHA; SUBUNIT; BINDING; CELLS;

D O I：

10.1016/j.bmcl.2012.06.049

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we describe the SAR of a novel series of 6-aryl-2-amino-triazolopyridines as potent and selective PI3K gamma inhibitors. The 6-aryl-triazolopyridine core was identified by chemoproteomic screening of a kinase focused library. Rapid chemical expansion around a bi-functional core identified the key features required for PI3K gamma activity and selectivity. The series was optimized to afford 43 (CZC19945), a potent PI3K gamma inhibitor with high oral bioavailability and selectivity over PI3K alpha and PI3K delta. Modification to the core afforded 53 (CZC24832) which showed increased selectivity over the entire kinome in particular over PI3K beta. (c) 2012 Elsevier Ltd. All rights reserved.

引用

页码：5257 / 5263

页数：7

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