title: Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2Inhibitor.
abstract: We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2inhibitors 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.
authors.affiliation: 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.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Measom
authors.affiliation: GlaxoSmithKline , Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Down
authors.affiliation: GlaxoSmithKline , Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hirst
authors.affiliation: Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, U.K.
authors.forename: Craig
authors.initials: C
authors.lastname: Jamieson
authors.affiliation: GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Manas
authors.affiliation: GlaxoSmithKline , Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Vipulkumar K
authors.initials: VK
authors.lastname: Patel
authors.affiliation: GlaxoSmithKline , Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
authors.forename: Don O
authors.initials: DO
authors.lastname: Somers
keywords: LpPLA2; bicyclo[1.1.1]pentane; bioisostere; cardiovascular disease; darapladib; physicochemical