Core Modifications of GSK3335103 toward Orally Bioavailable α v β 6 Inhibitors with Improved Synthetic Tractability

The α β integrin has been identified as a target for the treatment of fibrotic diseases, based on the role it has in activating TGF-β , a protein implicated in the pathogenesis of fibrosis. However, the development of orally bioavailable α β 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 β inhibitors, developing on two previously published α β 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 ( )- and as potent and orally bioavailable α β inhibitors with improved synthetic tractability.