Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2 Inhibitor

被引：186

作者：

Measom, Nicholas D. ^{[1
,2
]}

Down, Kenneth D. ^{[1
]}

Hirst, David J. ^{[1
]}

Jamieson, Craig ^{[2
]}

Manas, Eric S. ^{[3
]}

Patel, Vipulkumar K. ^{[1
]}

Somers, Don O. ^{[1
]}

机构：

[1] GlaxoSmithKline, Med Res Ctr, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England

[2] Univ Strathclyde, Dept Pure & Appl Chem, Thomas Graham Bldg,295 Cathedral St, Glasgow G1 1XL, Lanark, Scotland

[3] GlaxoSmithKline, 1250 South Collegeville Rd, Collegeville, PA 19426 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 01期

关键词：

LpPLA(2); bicyclo[1.1.1]pentane; bioisostere; darapladib; cardiovascular disease; physicochemical; ACTIVATING-FACTOR ACETYLHYDROLASE; LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE-A2; CARDIOVASCULAR OUTCOMES; BIOLOGICAL EVALUATION; MISSENSE MUTATION; A(2) INHIBITOR; RISK-FACTOR; DISEASE; INFLAMMATION; DEFICIENCY;

D O I：

10.1021/acsmedchemlett.6b00281

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA(2) inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.

引用

页码：43 / 48

页数：6

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