Discovery and\nDevelopment of Highly Potent and Orally\nBioavailable Nonpeptidic α<sub>v</sub>β<sub>6</sub> Integrin\nInhibitors

A series of 3-aryl((<i>S</i>)-3-fluoropyrrolidin-1-yl)butanoic\nacids were developed as potent orally bioavailable α<sub>v</sub>β<sub>6</sub> integrin inhibitors. Starting from a zwitterionic\npeptidomimetic series optimized for inhaled administration, the balancing\nof potency and passive permeability to achieve suitable oral agents\nthrough modification and exploration of aryl substituents and p<i>K</i><sub>a</sub> of the central cyclic amine is described.\n(<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\nacid was found to have highly desirable oral pharmacokinetic profiles\nin rat, dog, and minipig, with low to moderate clearance (26%, 7%,\nand 18% liver blood flow, respectively), moderate volumes of distribution\n(3.6, 1.4, and 0.9 L/kg, respectively), high to complete oral bioavailabilities,\nhigh α<sub>v</sub>β<sub>6</sub> integrin potency of pIC50\nof 8.0, and high solubility in physiological media (>2 mg/mL).\nEquating\nto the estimated human dose range of 10–75 mg b.i.d. to achieve\n90% α<sub>v</sub>β<sub>6</sub> target engagement at <i>C</i><sub>min</sub>, it was selected for further investigation\nas a potential therapeutic agent for the treatment of idiopathic pulmonary\nfibrosis.