Literature DB >> 28105273

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

Nicholas D Measom1, Kenneth D Down2, David J Hirst2, Craig Jamieson3, Eric S Manas4, Vipulkumar K Patel2, Don O Somers2.   

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.

Entities:  

Keywords:  LpPLA2; bicyclo[1.1.1]pentane; bioisostere; cardiovascular disease; darapladib; physicochemical

Year:  2016        PMID： 28105273      PMCID： PMC5238484          DOI： 10.1021/acsmedchemlett.6b00281

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


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