Core Modifications of GSK3335103 toward Orally Bioavailable α_vβ₆ Inhibitors with Improved Synthetic Tractability

The α_vβ₆ integrin has been identified as a target for the treatment of fibrotic diseases, based on the role it has in activating TGF-β₁, a protein implicated in the pathogenesis of fibrosis. However, the development of orally bioavailable α_vβ₆ inhibitors has proven challenging due to the zwitterionic pharmacophore required to bind to the RGD binding site. This work describes the design and development of a novel, orally bioavailable series of α_vβ₆ inhibitors, developing on two previously published α_vβ₆ inhibitors, GSK3008348 and GSK3335103. Strategies to reduce the basicity of the central ring nitrogen present in GSK3008348 were employed, while avoiding the synthetic complexity of the chiral, fluorine-containing quaternary carbon center contained in GSK3335103. Following initial PK studies, this series was optimized, aided by analysis of the physicochemical and in vitro PK properties, to deliver lead molecules (<i>S</i>)-<b>20</b> and <b>28</b> as potent and orally bioavailable α_vβ₆ inhibitors with improved synthetic tractability.