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

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• 作者：Asitha Abeywardane ; Gary Caviness ; Younggi Choi ; Derek Cogan ; ^{derek.cogan@boehringer-ingelheim.com" class="auth_mail" title="E-mail the corresponding author} ; 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
• 关键词：CCR10 ; CCL27 ; Psoriasis ; Contact hypersensitivity ; Structural alerts
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：26
• 期：21
• 页码：5277-5283
• 全文大小：3340 K

文摘

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 690 nM 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.