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.
        
Representative scheme of PAF-Acetylhydrolase structure and an image from PDBsum server
Databases
PDB-Sum
5LP1 Previously Class, Architecture, Topology and Homologous superfamily - PDB-Sum server
FSSP
5LP1Fold classification based on Structure-Structure alignment of Proteins - FSSP server