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.
Kevin Doyle  1 ,  Hans Lönn  2 ,  Helena Käck  2 ,  Amanda Van de Poël  1 ,  Steve Swallow  3 ,  Philip Gardiner  2 ,  Stephen Connolly  2 ,  James Root  2 ,  Cecilia Wikell  2 ,  Göran Dahl  2 ,  Kristina Stenvall  2 ,  Petra Johannesson  2
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.

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