2. Academic Validation
  3. 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

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

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: derek.cogan@boehringer-ingelheim.com.
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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