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

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

doi:10.1021/acs.jmedchem.6b01127

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

J Med Chem. 2016 Oct 27;59(20):9457-9472. doi: 10.1021/acs.jmedchem.6b01127. Epub 2016 Oct 11.

Affiliations

¹ Discovery, Charles River , Chesterford Research Park, Saffron Walden, Essex CB10 1XL, U.K.
² AstraZeneca Gothenburg , Pepparedsleden 1, Mölndal 431 83, Sweden.
³ AstraZeneca Alderley Park , Macclesfield, Cheshire SK10 4TG, U.K.

PMID: 27690432
DOI: 10.1021/acs.jmedchem.6b01127

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.

MeSH terms

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

Substances

Benzoxazoles
Oxazepines
Protease Inhibitors
brensocatib
CTSC protein, human
Cathepsin C