The discovery and evaluation of 3-amino-2(1H)-pyrazinones as a novel series of selective p38α MAP kinase inhibitors

  • Bioorg Med Chem Lett. 2020 Sep 15;30(18):127412. doi: 10.1016/j.bmcl.2020.127412.
Piotr Raubo  1 ,  Richard Evans  2 ,  Paul Willis  2
Affiliations
  • 1. Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK; AstraZeneca R&D Charnwood, Loughborough, UK. Electronic address: [email protected].
  • 2. AstraZeneca R&D Charnwood, Loughborough, UK.
PMID: 32717614 DOI: 10.1016/j.bmcl.2020.127412
Abstract

The discovery and optimisation of a novel series of potent and selective p38α inhibitors is described. Evaluating the structure-activity relationship of an aminoalkyl substituent at the 3 position of the 2(1H)-pyrazinone core, p38α potency was increased 20000-fold. The most advanced compound (25) demonstrated excellent in vivo properties suitable for an inhaled route of administration.

Keywords
AZD6703; AZD7624; COPD; Inflammation; Kinases; P38α.
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