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

Abstract

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.

• Authors: Kevin Doyle, Hans Lönn, Helena Käck, Amanda Van de Poël, Steve Swallow, Philip Gardiner, Stephen Connolly, James Root, Cecilia Wikell, Göran Dahl, Kristina Stenvall, Petra Johannesson
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 59 Issue 20 Pg. 9457-9472 (Oct 27 2016) ISSN: 1520-4804 [Electronic] United States
• PMID: 27690432 (Publication Type: Journal Article)

Chemical References

• Benzoxazoles
• Oxazepines
• Protease Inhibitors
• brensocatib
• CTSC protein, human
• Cathepsin C

Topics

• Administration, Oral
• Animals
• Benzoxazoles (administration & dosage, chemistry, pharmacology)
• Cathepsin C (antagonists & inhibitors, metabolism)
• Dogs
• Dose-Response Relationship, Drug
• Drug Discovery
• Humans
• Mice
• Molecular Structure
• Oxazepines (administration & dosage, chemistry, pharmacology)
• Protease Inhibitors (administration & dosage, chemistry, pharmacology)
• Rabbits
• Rats
• Structure-Activity Relationship
• U937 Cells