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.pdfVIP

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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.pdf

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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.pdf

Bioorganic Medicinal Chemistry Letters 26 (2016) 5277–5283 Contents lists available at ScienceDirect Bioorganic Medicinal Chemistry Letters journal homepage: /locate/bmcl N-Arylsulfonyl-a-amino carboxamides are potent and selective inhibitors of the chemokine receptor CCR10 that show ef?cacy in the murine DNFB model of contact hypersensitivity Asitha Abeywardane, Gary Caviness, Younggi Choi, Derek Cogan ?, Amy Gao, Daniel Goldberg, Alexander Heim-Riether, Debra Jeanfavre, Elliott Klein, Jennifer A. Kowalski, Wang Mao, Craig Miller, Neil Moss, Philip Ramsden, Ernest Raymond, Donna Skow, Lana Smith-Keenan, Roger J. Snow, Frank Wu, Jiang-Ping Wu, Yang Yu Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridge?eld, CT 06877, USA article info Article history: Received 29 June 2016 Revised 15 September 2016 Accepted 16 September 2016 Available online 21 September 2016 Keywords: CCR10 CCL27 Psoriasis Contact hypersensitivity Structural alerts abstract Compound 1 ((4-amino-3,5-dichlorophenyl)-1-(4-methylpiperidin-1-yl)-4-(2-nitroimidazol-1-yl)-1oxobutane-2-sulfonamido) was discovered to be a 690 nM antagonist of human CCR10 Ca2+ ?ux. Optimization delivered (2R)-4-(2-cyanopyrrol-1-yl)-S-(1H-indol-4-yl)-1-(4-methylpiperidin-1-yl)-1oxobutane-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 ef?cacious in the murine DNFB model of contact hypersensitivity. The ef?cacy of this compound provides further evidence for the role of CCR10 in dermatological in?ammatory conditions. ó 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// /licenses/by/4.0/). The control of T cell homing to different tissues during in?ammation is the result of the in