Investigation of a bicyclo[1.1.1]pentane as a phenyl replacement within an LpPLA2 inhibitor

Measom, Nicholas and Down, Kenneth D. and Hirst, David J. and Jamieson, Craig and Manas, Eric S. and Patel, Vipulkumar K. and Somers, Donald O. (2016) Investigation of a bicyclo[1.1.1]pentane as a phenyl replacement within an LpPLA2 inhibitor. ACS Medicinal Chemistry Letters, 7. (https://doi.org/10.1021/acsmedchemlett.6b00281)

[thumbnail of Measom-etal-ACSMCL2016-bicyclo[1.1.1]pentane-as-a-phenyl-replacement-within-an-LpPLA2-inhibitor]
Preview
 Text. Filename: Measom_etal_ACSMCL2016_bicyclo_1.1.1_pentane_as_a_phenyl_replacement_within_an_LpPLA2_inhibitor.pdf
Accepted Author Manuscript
Download (1MB)| Preview

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.

CORE (COnnecting REpositories)