Structure Activity Relationships of α_v Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents

Antagonism of α_vβ₆ is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an α_vβ₃ antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved α_vβ₆ activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds <b>33S</b> and <b>43E1</b> are pan α_v antagonists having <i>ca.</i> 100 nM potency against α_vβ_3, α_vβ_5, α_vβ₆, and α_vβ₈ in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC₅₀ values between the integrins in question) for α_vβ₃ and α_vβ₅