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

Nicholas Measom, Kenneth D. Down, David J. Hirst, Craig Jamieson, Eric S. Manas, Vipulkumar K. Patel, Donald O. Somers

Research output: Contribution to journalArticle

42 Citations (Scopus)
58 Downloads (Pure)

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.
Original languageEnglish
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume7
DOIs
Publication statusPublished - 15 Nov 2016

Keywords

  • LpPLA2
  • bicyclo[1.1.1]pentane
  • bioisostere
  • darapladib
  • cardiovascular disease
  • physicochemical
  • bioisosteric phenyl replacements

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