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

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.

SUBMITTER: Measom ND

PROVIDER: S-EPMC5238484 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Measom Nicholas D ND Down Kenneth D KD Hirst David J DJ Jamieson Craig C Manas Eric S ES Patel Vipulkumar K VK Somers Don O DO

ACS medicinal chemistry letters 20161115 1

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 ...[more]

PMID: 28105273

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