Discovery of Pyrazole-Containing RGD Mimics with Anti-Fibrotic Efficacy in the Unilateral Ureteral Obstruction Mouse Model.

Fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), metabolic dysfunction-associated steatohepatitis (MASH), and kidney fibrosis represent a major unmet medical need. IPF patients have a mean survival of only 2-5 years, and despite this critical need, only two drugs have been approved in the past decade. These therapies offer limited efficacy and poor tolerability, underscoring the need for better options. Targeting αV integrins has emerged as a promising strategy, supported by strong preclinical data. While αVβ1/6 inhibitors are in clinical trials, our approach focused on developing pan-αV inhibitors with selectivity over αVβ8 and αIIbβ3 and oral pharmacokinetics. Through lead optimization, we identified compound 14, a potent inhibitor of αVβ1, αVβ3, αVβ5, and αVβ6, with high selectivity, oral bioavailability, and low IV clearance. In a mouse unilateral ureteral obstruction model, oral dosing of 14 (10 mg/kg/day for 8 days) reduced total collagen by 25% versus vehicle.