Discovery and Development of Highly Potent and Orally Bioavailable Nonpeptidic α v β 6 Integrin Inhibitors

• Published in: Journal of medicinal chemistry 2024-10, Vol.67 (19), p.17497-17519
• Main Authors: Procopiou, Panayiotis A, Barrett, John, Crawford, Matthew H J, Hatley, Richard J D, Hancock, Ashley P, Pritchard, John M, Rowedder, James E, Copley, Royston C B, Slack, Robert J, Sollis, Steven L, Thorp, Lee R, Lippa, Rhys A, Macdonald, Simon J F, Barrett, Tim N
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01430

A series of 3-aryl(( )-3-fluoropyrrolidin-1-yl)butanoic acids were developed as potent orally bioavailable α β integrin inhibitors. Starting from a zwitterionic peptidomimetic series optimized for inhaled administration, the balancing of potency and passive permeability to achieve suitable oral agents through modification and exploration of aryl substituents and p of the central cyclic amine is described. ( )-4-(( )-3-Fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-3-(3-(2-methoxyethoxy)phenyl)butanoic acid was found to have highly desirable oral pharmacokinetic profiles in rat, dog, and minipig, with low to moderate clearance (26%, 7%, and 18% liver blood flow, respectively), moderate volumes of distribution (3.6, 1.4, and 0.9 L/kg, respectively), high to complete oral bioavailabilities, high α β integrin potency of pIC50 of 8.0, and high solubility in physiological media (>2 mg/mL). Equating to the estimated human dose range of 10-75 mg b.i.d. to achieve 90% α β target engagement at , it was selected for further investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.