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 (https://doi.org/10.1021/acs.jmedchem.9b00819)

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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.

ORCID iDs

Barrett, Tim N., Taylor, Jonathan A. ORCID logoORCID: https://orcid.org/0000-0003-2305-0708, Barker, Daniel, Procopiou, Panayiotis A., Thompson, James D. F., Barrett, John, Le, Joelle, Lynn, Sean M., Pogany, Peter, Pratley, Cassie, Pritchard, John M., Roper, James A., Rowedder, James E., Slack, Robert J., Vitulli, Giovanni, Macdonald, Simon J. F. and Kerr, William J. ORCID logoORCID: https://orcid.org/0000-0002-1332-785X;
  • Item type:Article
    ID code:69425
    Dates:
    Date
    Event
    22 August 2019
    Published
    5 August 2019
    Published Online
    20 May 2019
    Accepted
    Subjects:Science > Chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:20 Aug 2019 11:05
    Last modified:11 Nov 2024 12:24
    URI:https://strathprints.strath.ac.uk/id/eprint/69425
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