10.1021/acsmedchemlett.6b00281.s001 Nicholas D. Measom Nicholas D. Measom Kenneth D. Down Kenneth D. Down David J. Hirst David J. Hirst Craig Jamieson Craig Jamieson Eric S. Manas Eric S. Manas Vipulkumar K. Patel Vipulkumar K. Patel Don O. Somers Don O. Somers Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA<sub>2</sub> Inhibitor American Chemical Society 2016 bicyclo moiety physicochemical profile data investigation LpPLA 2 Inhibitor LpPLA 2 inhibitors transformation synthesis Potency bioisosteric phenyl replacements incorporation isostere X-ray dichlorocarbene insertion target compounds Bicyclo Phenyl Replacement bioisosteric counterparts 2016-11-15 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Investigation_of_a_Bicyclo_1_1_1_pentane_as_a_Phenyl_Replacement_within_an_LpPLA_sub_2_sub_Inhibitor/4263362 We describe the incorporation of a bicyclo[1.1.1]­pentane moiety within two known LpPLA<sub>2</sub> 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.