Discovery of (S)-3-(3-(3,5-Dimethyl-1 H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid, a nonpeptidic αvβ6 integrin inhibitor for the inhaled treatment of idiopathic pulmonary fibrosis

Panayiotis A. Procopiou, Niall A. Anderson, John Barrett, Tim N. Barrett, Matthew H. J. Crawford, Brendan J. Fallon, Ashley P. Hancock, Joelle Le, Seble Lemma, Richard P. Marshall, Josie Morrell, John M. Pritchard, James E. Rowedder, Paula Saklatvala, Robert J. Slack, Steven L. Sollis, Colin J. Suckling, Lee R. Thorp, Giovanni Vitulli, Simon J. F. Macdonald

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of (R)-BINAP to a crotonate ester to provide the (S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αvβ1, αvβ3, αvβ5, αvβ6, and αvβ8 integrins. Numerous analogs with high affinity and selectivity for the αvβ6 integrin were identified. The analog (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for αvβ6 integrin in a radioligand binding assay (pKi = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further clinical investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.

Original languageEnglish
Pages (from-to)8417-8443
Number of pages27
JournalJournal of Medicinal Chemistry
Volume61
Issue number18
Early online date14 Sep 2018
DOIs
Publication statusPublished - 27 Sep 2018

Keywords

  • idiopathic pulmonary fibrosis
  • integrins
  • inhaled treatment

Fingerprint

Dive into the research topics of 'Discovery of (S)-3-(3-(3,5-Dimethyl-1 H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid, a nonpeptidic α<sub>v</sub>β<sub>6</sub> integrin inhibitor for the inhaled treatment of idiopathic pulmonary fibrosis'. Together they form a unique fingerprint.

Cite this