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.
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.
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Asitha
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Abeywardane
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Gary
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Caviness
Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA.
Younggi
Y
Choi
Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. Electronic address: derek.cogan@boehringer-ingelheim.com.
Derek
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Cogan
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Amy
A
Gao
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Goldberg
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Heim-Riether
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Jeanfavre
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Klein
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Kowalski
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Mao
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Miller
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Moss
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Ramsden
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Raymond
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Skow
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Smith-Keenan
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Roger J
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Snow
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Frank
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Wu
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Jiang-Ping
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Wu
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Yu
D000577:Amides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry; D002460:Cell Line; D003877:Dermatitis, Contact / Q000188:drug therapy*; D004139:Dinitrofluorobenzene / Q000633:toxicity*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D054447:Receptors, CCR10 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000577:Amides; D002264:Carboxylic Acids; C515707:Ccr10 protein, mouse; D054447:Receptors, CCR10; D004139:Dinitrofluorobenzene
CCL27; CCR10; Contact hypersensitivity; Psoriasis; Structural alerts