title: Synthesis and structure-activity relationship of a novel sulfone series of TNF-alpha converting enzyme inhibitors.
abstract: Replacement of the amide functionality in IM491 (N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]5-piperidinecarboxamide) with a sulfonyl group led to a new series of alpha,beta-cyclic and beta,beta-cyclic gamma-sulfonyl hydroxamic acids, which were potent TNF-alpha converting enzyme (TACE) inhibitors. Among them, inhibitor 4b (N-hydroxy-(4S,5S)-1-methyl-5-[[4-(2-methyl-4-quinolinylmethoxy)phenyl]sulfonylmethyl]-4-pyrrolidinecarboxamide) exhibited IC50 values of < 1 nM and 180 nM in porcine TACE (pTACE) and cell assays, respectively, with excellent selectivity over MMP-1, -2, -9 and -13 and was orally bioavailable with an F value of 46% in mice.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. cxue@incyte.com
authors.forename: Chu-Biao
authors.initials: CB
authors.lastname: Xue
authors.forename: Xiao-Tao
authors.initials: XT
authors.lastname: Chen
authors.forename: Xiaohua
authors.initials: X
authors.lastname: He
authors.forename: John
authors.initials: J
authors.lastname: Roderick
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Corbett
authors.forename: Bahman
authors.initials: B
authors.lastname: Ghavimi
authors.forename: Rui-Qin
authors.initials: RQ
authors.lastname: Liu
authors.forename: Maryanne B
authors.initials: MB
authors.lastname: Covington
authors.forename: Mingxin
authors.initials: M
authors.lastname: Qian
authors.forename: Maria D
authors.initials: MD
authors.lastname: Ribadeneira
authors.forename: Krishna
authors.initials: K
authors.lastname: Vaddi
authors.forename: James
authors.initials: J
authors.lastname: Trzaskos
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: James J-W
authors.initials: JJ
authors.lastname: Duan
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D018938:Caco-2 Cells; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D011480:Protease Inhibitors; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat