Balancing hERG affinity and absorption in the discovery of AZD5672, an orally active CCR5 antagonist for the treatment of rheumatoid arthritis

被引：29

作者：

Cumming, John G. ^{[1
]}

Tucker, Howard ^{[1
]}

Oldfield, John ^{[1
]}

Fielding, Colin ^{[1
]}

Highton, Adrian ^{[1
]}

Faull, Alan ^{[1
]}

Wild, Martin ^{[1
]}

Brown, Dearg ^{[1
]}

Wells, Stuart ^{[1
]}

Shaw, John ^{[1
]}

机构：

[1] AstraZeneca, Resp & Inflammat Res Area, Macclesfield SK10 4TG, Cheshire, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 04期

关键词：

CCR5; antagonist; Chemokine receptor; hERG; SMALL-MOLECULE INHIBITOR; CHEMOKINE RECEPTOR CCR5; PERIPHERAL-BLOOD; SYNOVIAL TISSUE; PART; MODULATORS; SAR; LIPOPHILICITY; UK-427,857; EXPRESSION;

D O I：

10.1016/j.bmcl.2011.12.117

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：

Modifications to a series of potent and selective substituted 1-(3,3-diphenylpropyl)-piperidine phenylacetamide CCR5 antagonists were explored with the aim of reducing affinity at the hERG cardiac ion channel. Replacement of one aromatic ring in the diphenylpropyl region with less lipophilic, saturated heterocyclic rings and subsequent optimisation of the other phenyl ring led to the identification of clinical compound AZD5672 which retained excellent potency while reducing hERG affinity. Modulating lipophilicity affected the interplay between potency, hERG affinity and absorption. AZD5672 was found to have an acceptable balance of these properties and was progressed to a phase II clinical trial to test the hypothesis that inhibition of CCR5 will bring benefits in the treatment of rheumatoid arthritis. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：1655 / 1659

页数：5

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