The discovery of potent, orally bioavailable pyrazolo and triazolopyrimidine CXCR2 receptor antagonists

被引：21

作者：

Porter, David W. ^{[1
]}

Bradley, Michelle ^{[1
]}

Brown, Zarin ^{[1
]}

Canova, Riccardo ^{[2
]}

Charlton, Steven ^{[1
]}

Cox, Brian ^{[1
]}

Hunt, Peter ^{[1
]}

Kolarik, David ^{[2
]}

Lewis, Sarah ^{[1
]}

O'Connor, Des ^{[1
]}

Reilly, John ^{[1
]}

Spanka, Carsten ^{[2
]}

Tedaldi, Lauren ^{[1
]}

Watson, Simon J. ^{[1
]}

Wermuth, Roland ^{[2
]}

Press, Neil J. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, Horsham Res Ctr, Horsham RH12 5AB, W Sussex, England

[2] Novartis Inst BioMed Res, CH-4056 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 01期

关键词：

CXCR2; Chemokines; Pyrazolopyrimidine; Triazolopyrimidine; Neutrophils; COPD; HIT-TO-LEAD; PULMONARY-DISEASE; INTERLEUKIN-8;

D O I：

10.1016/j.bmcl.2013.11.074

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A hit-to-lead optimisation programme was carried out on the Novartis archive screening hit, pyrazolopyrimidine 2-methyl-5-((phenylthio)methyl)pyrazolo[1,5-a]pyrimidin-7-ol 1, resulting in the discovery of CXCR2 receptor antagonist 2-benzyl-5-(((2,3-difluorophenyl)thio)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol 14. The SAR was investigated by systematic variation of the pendant thiol, alkyl and pyrimidinol groups. Replacement of the pyrazolopyrimidine core with a triazolo alternative led to a dual series of antagonists with favourable biological and pharmacokinetic properties. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：72 / 76

页数：5

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