Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986)

A novel series of second generation DPP1 inhibitors free from aorta binding liabilities found for earlier compound series was discovered. This work culminated in the identification of compound 30 (AZD7986) as a highly potent, reversible, and selective clinical candidate for COPD, with predicted human PK properties suitable for once daily human dosing.