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.

LanguageEnglish
Pages7543-7556
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number16
Early online date5 Aug 2019
DOIs
Publication statusPublished - 22 Aug 2019

Fingerprint

Integrin alpha6
Integrin alpha Chains
Betaine
Methylation
Pharmacokinetics
Cell adhesion
Ammonium Compounds
Cell Adhesion
Integrins
Assays
pyrrolidine

Keywords

  • idiopathic pulmonary fibrosis
  • stereoselective methylation
  • ammonium betaine 7

Cite this

Barrett, Tim N. ; Taylor, Jonathan A. ; 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. ; Kerr, William J. / 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. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 16. pp. 7543-7556.
@article{a800b996b87f47129c9b57ace8ed66de,
title = "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",
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.",
keywords = "idiopathic pulmonary fibrosis, stereoselective methylation, ammonium betaine 7",
author = "Barrett, {Tim N.} and Taylor, {Jonathan A.} and Daniel Barker and Procopiou, {Panayiotis A.} and Thompson, {James D. F.} and John Barrett and Joelle Le and Lynn, {Sean M.} and Peter Pogany and Cassie Pratley and Pritchard, {John M.} and Roper, {James A.} and Rowedder, {James E.} and Slack, {Robert J.} and Giovanni Vitulli and Macdonald, {Simon J. F.} and Kerr, {William J.}",
year = "2019",
month = "8",
day = "22",
doi = "10.1021/acs.jmedchem.9b00819",
language = "English",
volume = "62",
pages = "7543--7556",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "16",

}

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.; Taylor, Jonathan A.; 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.; Kerr, William J.

In: Journal of Medicinal Chemistry, Vol. 62, No. 16, 22.08.2019, p. 7543-7556.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Barrett, Tim N.

AU - Taylor, Jonathan A.

AU - Barker, Daniel

AU - Procopiou, Panayiotis A.

AU - Thompson, James D. F.

AU - Barrett, John

AU - Le, Joelle

AU - Lynn, Sean M.

AU - Pogany, Peter

AU - Pratley, Cassie

AU - Pritchard, John M.

AU - Roper, James A.

AU - Rowedder, James E.

AU - Slack, Robert J.

AU - Vitulli, Giovanni

AU - Macdonald, Simon J. F.

AU - Kerr, William J.

PY - 2019/8/22

Y1 - 2019/8/22

N2 - 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.

AB - 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.

KW - idiopathic pulmonary fibrosis

KW - stereoselective methylation

KW - ammonium betaine 7

U2 - 10.1021/acs.jmedchem.9b00819

DO - 10.1021/acs.jmedchem.9b00819

M3 - Article

VL - 62

SP - 7543

EP - 7556

JO - Journal of Medicinal Chemistry

T2 - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 16

ER -