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

Barrett, Tim N. and Taylor, Jonathan A. and Barker, Daniel and Procopiou, Panayiotis A. and Thompson, James D. F. and Barrett, John and Le, Joelle and Lynn, Sean M. and Pogany, Peter and Pratley, Cassie and Pritchard, John M. and Roper, James A. and Rowedder, James E. and Slack, Robert J. and Vitulli, Giovanni and Macdonald, Simon J. F. and Kerr, William J. (2019) 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. Journal of Medicinal Chemistry, 62 (16). pp. 7543-7556. ISSN 0022-2623

[img] Text (Barrett-etal-JMC-2019-Profile-of-a-highly-selective-quaternized-pyrrolidine-betaine)
Barrett_etal_JMC_2019_Profile_of_a_highly_selective_quaternized_pyrrolidine_betaine.pdf
Accepted Author Manuscript
Restricted to Repository staff only until 5 August 2020.

Download (1MB) | Request a copy from the Strathclyde author

    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.