Potent and orally bioavailable CCR4 antagonists: Synthesis and structure-activity relationship study of 2-aminoquinazolines

Bioorg Med Chem. 2009 Jan 1;17(1):64-73. doi: 10.1016/j.bmc.2008.11.020. Epub 2008 Nov 17.

Abstract

Starting with a series of CC chemokine receptor-4 (CCR4) antagonists developed in a previous study, the potency was improved by replacing the pyrrolidine moiety of N-(4-chlorophenyl)-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine 2 with a 3-(hydroxymethyl)piperidine. The resulting compound (1'-{4-[(4-chlorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}-1,4'-bipiperidin-3-yl)methanol 8ic was a strong inhibitor of human/mouse chemotaxis. Oral administration of 8ic showed anti-inflammatory activity in a murine model of acute dermatitis (oxazolone-induced contact hypersensitivity test) in a dose-dependent manner.

MeSH terms

  • Administration, Oral
  • Amines
  • Animals
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / pharmacokinetics
  • Chemotaxis / drug effects
  • Dermatitis / drug therapy
  • Disease Models, Animal
  • Humans
  • Mice
  • Piperidines
  • Quinazolines / pharmacokinetics*
  • Quinazolines / pharmacology
  • Receptors, CCR4 / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Amines
  • Anti-Inflammatory Agents
  • Piperidines
  • Quinazolines
  • Receptors, CCR4