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ID: ALA3862010
Journal: Bioorg Med Chem Lett
Title: 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.
Authors: Abeywardane A, Caviness G, Choi Y, Cogan D, Gao A, Goldberg D, Heim-Riether A, Jeanfavre D, Klein E, Kowalski JA, Mao W, Miller C, Moss N, Ramsden P, Raymond E, Skow D, Smith-Keenan L, Snow RJ, Wu F, Wu JP, Yu Y.
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.
CiteXplore: 27692854