title: Rational design, synthesis and structure-activity relationships of a cyclic succinate series of TNF-alpha converting enzyme inhibitors. Part 2: lead optimization.
abstract: Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-[[4-(4-quinolinyloxymethyl)anilinyl]carbonyl]-1-cyclohexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing TACE inhibitors with potent activity in the inhibition of TNF-alpha release in the whole blood assay (WBA). The most potent analogue IM491 [N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]-5-piperidinecarboxamide] exhibited an IC(50) value of 20 nM in WBA with excellent selectivity over MMP-1, -2 and -9 and is orally bioavailable with an F value of 43% in beagle dogs.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. cxue@incite.com
authors.forename: Chu-Biao
authors.initials: CB
authors.lastname: Xue
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: James J-W
authors.initials: JJ
authors.lastname: Duan
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: David D
authors.initials: DD
authors.lastname: Christ
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: James M
authors.initials: JM
authors.lastname: Trzaskos
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Magolda
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013386:Succinates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013386:Succinates; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein