Profile of a highly selective quaternized pyrrolidine betaine αvβ6 integrin inhibitor - (3S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((1S and 1R,3R)-1-methyl-3-(2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-ium-1-yl)butanoate synthesized by stereoselective methylation

Tim N. Barrett, Jonathan A. Taylor, Daniel Barker, Panayiotis A. Procopiou, James D. F. Thompson, John Barrett, Joelle Le, Sean M. Lynn, Peter Pogany, Cassie Pratley, John M. Pritchard, James A. Roper, James E. Rowedder, Robert J. Slack, Giovanni Vitulli, Simon J. F. Macdonald, William J. Kerr

Research output: Contribution to journalArticle

Abstract

A quaternary ammonium betaine 7 is described which shows exceptional potency and selectivity (1.4 to >3 logs) for the α vβ 6 integrin receptor over the other α v integrins as determined in cell adhesion assays. 7 is prepared by remarkably stereoselective methylation, the origins of which are discussed. The chemical, biological, physicochemical, and pharmacokinetic properties of 7 and its docking into α vβ 6 are described along with related analogues.

Original languageEnglish
Pages (from-to)7543-7556
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number16
Early online date5 Aug 2019
DOIs
Publication statusPublished - 22 Aug 2019

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Keywords

  • idiopathic pulmonary fibrosis
  • stereoselective methylation
  • ammonium betaine 7

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