N-Arylsulfonyl-α-amino carboxamides are potent and selective inhibitors of the chemokine receptor CCR10 that show efficacy in the murine DNFB model of contact hypersensitivity

Bioorg Med Chem Lett. 2016 Nov 1;26(21):5277-5283. doi: 10.1016/j.bmcl.2016.09.047. Epub 2016 Sep 21.

Abstract

Compound 1 ((4-amino-3,5-dichlorophenyl)-1-(4-methylpiperidin-1-yl)-4-(2-nitroimidazol-1-yl)-1-oxobutane-2-sulfonamido) was discovered to be a 690nM antagonist of human CCR10 Ca2+ flux. Optimization delivered (2R)-4-(2-cyanopyrrol-1-yl)-S-(1H-indol-4-yl)-1-(4-methylpiperidin-1-yl)-1-oxobutane-2-sulfonamido (eut-22) that is 300 fold more potent a CCR10 antagonist than 1 and eliminates potential toxicity, mutagenicity, and drug-drug-interaction liabilities often associated with nitroaryls and anilines. eut-22 is highly selective over other GPCR's, including a number of other chemokine receptors. Finally, eut-22 is efficacious in the murine DNFB model of contact hypersensitivity. The efficacy of this compound provides further evidence for the role of CCR10 in dermatological inflammatory conditions.

Keywords: CCL27; CCR10; Contact hypersensitivity; Psoriasis; Structural alerts.

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology*
  • Amides / therapeutic use
  • Animals
  • Carboxylic Acids / chemistry
  • Cell Line
  • Dermatitis, Contact / drug therapy*
  • Dinitrofluorobenzene / toxicity*
  • Disease Models, Animal*
  • Humans
  • Mice
  • Receptors, CCR10 / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Amides
  • Carboxylic Acids
  • Ccr10 protein, mouse
  • Receptors, CCR10
  • Dinitrofluorobenzene