Boronic acid-containing aminopyridine- and aminopyrimidinecarboxamide CXCR1/2 antagonists: Optimization of aqueous solubility and oral bioavailability

Bioorg Med Chem Lett. 2015 Sep 15;25(18):3793-7. doi: 10.1016/j.bmcl.2015.07.090. Epub 2015 Jul 30.

Abstract

The chemokine receptors CXCR1 and CXCR2 are important pharmaceutical targets due to their key roles in inflammatory diseases and cancer progression. We have previously identified 2-[5-(4-fluoro-phenylcarbamoyl)-pyridin-2-ylsulfanylmethyl]-phenylboronic acid (SX-517) and 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide (SX-576) as potent non-competitive boronic acid-containing CXCR1/2 antagonists. Herein we report the synthesis and evaluation of aminopyridine and aminopyrimidine analogs of SX-517 and SX-576, identifying (2-{(benzyl)[(5-boronic acid-2-pyridyl)methyl]amino}-5-pyrimidinyl)(4-fluorophenylamino)formaldehyde as a potent chemokine antagonist with improved aqueous solubility and oral bioavailability.

Keywords: Antagonist; Asthma; COPD; CXCR1; CXCR2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Biological Availability
  • Boronic Acids / administration & dosage
  • Boronic Acids / chemistry
  • Boronic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Niacinamide / administration & dosage
  • Niacinamide / analogs & derivatives*
  • Niacinamide / chemistry
  • Niacinamide / pharmacology
  • Receptors, Interleukin-8A / antagonists & inhibitors*
  • Receptors, Interleukin-8B / antagonists & inhibitors*
  • Solubility
  • Structure-Activity Relationship
  • Water / chemistry

Substances

  • 2-(5-(4-fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl)phenylboronic acid
  • Boronic Acids
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B
  • SX-576
  • Water
  • Niacinamide