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.
Asitha Abeywardane  1 ,  Gary Caviness  1 ,  Younggi Choi  1 ,  Derek Cogan  2 ,  Amy Gao  1 ,  Daniel Goldberg  1 ,  Alexander Heim-Riether  1 ,  Debra Jeanfavre  1 ,  Elliott Klein  1 ,  Jennifer A Kowalski  1 ,  Wang Mao  1 ,  Craig Miller  1 ,  Neil Moss  1 ,  Philip Ramsden  1 ,  Ernest Raymond  1 ,  Donna Skow  1 ,  Lana Smith-Keenan  1 ,  Roger J Snow  1 ,  Frank Wu  1 ,  Jiang-Ping Wu  1 ,  Yang Yu  1
Affiliations
  • 1. Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA.
  • 2. Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. Electronic address: [email protected].
PMID: 27692854 DOI: 10.1016/j.bmcl.2016.09.047
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.
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