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

Nicholas D Measom; Kenneth D Down; David J Hirst; Craig Jamieson; Eric S Manas; Vipulkumar K Patel; Don O Somers

doi:10.1021/acsmedchemlett.6b00281

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

ACS Med Chem Lett. 2016 Nov 15;8(1):43-48. doi: 10.1021/acsmedchemlett.6b00281. eCollection 2017 Jan 12.

Authors

Nicholas D Measom¹, Kenneth D Down², David J Hirst², Craig Jamieson³, Eric S Manas⁴, Vipulkumar K Patel², Don O Somers²

Affiliations

¹ GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.; Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, U.K.
² GlaxoSmithKline , Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
³ Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, U.K.
⁴ GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.

Abstract

We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA₂ 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.

Keywords: LpPLA2; bicyclo[1.1.1]pentane; bioisostere; cardiovascular disease; darapladib; physicochemical.