Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model

Bioorg Med Chem Lett. 2015 Jun 1;25(11):2280-4. doi: 10.1016/j.bmcl.2015.04.041. Epub 2015 Apr 23.

Abstract

Blockade of undesired neutrophil migration to sites of inflammation remains an area of substantial pharmaceutical interest. To effect this blockade, a validated therapeutic target is antagonism of the chemokine receptor CXCR2. Herein we report the discovery of 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide 6, an antagonist with activity at both CXCR1 and CXCR2 receptors (IC50 values 31 and 21 nM, respectively). Compound 6 exhibited potent inhibition of neutrophil influx in a rat model of pulmonary inflammation, and is hypothesized to interact with a unique intracellular binding site on CXCR2. Compound 6 (SX-576) is undergoing further investigation as a potential therapy for pulmonary inflammation.

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

Publication types

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

MeSH terms

  • Animals
  • Boronic Acids / chemistry*
  • Boronic Acids / therapeutic use
  • Computational Biology
  • Drug Design
  • Inflammation / chemically induced
  • Inflammation / drug therapy
  • Lung Diseases / chemically induced
  • Lung Diseases / drug therapy
  • Molecular Structure
  • Niacinamide / analogs & derivatives*
  • Niacinamide / chemistry
  • Niacinamide / therapeutic use
  • Ozone / toxicity
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Interleukin-8A / antagonists & inhibitors*
  • Receptors, Interleukin-8B / antagonists & inhibitors*
  • Receptors, Interleukin-8B / chemistry

Substances

  • Boronic Acids
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B
  • SX-576
  • Niacinamide
  • Ozone