Core Modifications\nof GSK3335103 toward Orally\nBioavailable α<sub>v</sub>β<sub>6</sub> Inhibitors with\nImproved Synthetic Tractability

The α<sub>v</sub>β<sub>6</sub> integrin has\nbeen identified\nas a target for the treatment of fibrotic diseases, based on the role\nit has in activating TGF-β<sub>1</sub>, a protein implicated\nin the pathogenesis of fibrosis. However, the development of orally\nbioavailable α<sub>v</sub>β<sub>6</sub> inhibitors has\nproven challenging due to the zwitterionic pharmacophore required\nto bind to the RGD binding site. This work describes the design and\ndevelopment of a novel, orally bioavailable series of α<sub>v</sub>β<sub>6</sub> inhibitors, developing on two previously\npublished α<sub>v</sub>β<sub>6</sub> inhibitors, GSK3008348\nand GSK3335103. Strategies to reduce the basicity of the central ring\nnitrogen present in GSK3008348 were employed, while avoiding the synthetic\ncomplexity of the chiral, fluorine-containing quaternary carbon center\ncontained in GSK3335103. Following initial PK studies, this series\nwas optimized, aided by analysis of the physicochemical and in vitro\nPK properties, to deliver lead molecules (<i>S</i>)-<b>20</b> and <b>28</b> as potent and orally bioavailable α<sub>v</sub>β<sub>6</sub> inhibitors with improved synthetic tractability.