Discovery and Development of Highly Potent and Orally Bioavailable Nonpeptidic α_vβ₆ Integrin Inhibitors

A series of 3-aryl((<i>S</i>)-3-fluoropyrrolidin-1-yl)butanoic acids were developed as potent orally bioavailable α_vβ₆ 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<i>K</i>_a of the central cyclic amine is described. (<i>S</i>)-4-((<i>S</i>)-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_vβ₆ 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_vβ₆ target engagement at <i>C</i>_min, it was selected for further investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.