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. Epub 2020 Jul 15.

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.

MeSH terms

  • Administration, Inhalation
  • Alkanes / chemistry
  • Amines / chemistry
  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / adverse effects
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / pharmacokinetics
  • Benzamides / pharmacology
  • Dogs
  • Drug Evaluation, Preclinical
  • Humans
  • Inflammation / drug therapy*
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
  • Models, Molecular
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pyrazines / chemical synthesis*
  • Pyrazines / pharmacology
  • Quinazolines / pharmacology
  • Rats
  • Structure-Activity Relationship

Substances

  • Alkanes
  • Amines
  • Anti-Inflammatory Agents
  • Benzamides
  • N-cyclopropyl-4-methyl-3-(6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl)benzamide
  • Protein Kinase Inhibitors
  • Pyrazines
  • Quinazolines
  • AZD7624
  • Mitogen-Activated Protein Kinase 14