title: Rational design, synthesis and structure-activity relationships of a cyclic succinate series of TNF-alpha converting enzyme inhibitors. Part 1: lead identification.
abstract: Rational design based on the broad spectrum MMP inhibitor CGS 27023A led to the identification of a novel series of cyclic succinate TACE inhibitors. As a mixture of two enantiomers, the lead compound 17b exhibited potent enzyme activity (IC(50)=8 nM) in the inhibition of porcine TNF-alpha converting enzyme (pTACE) and excellent selectivity over aggrecanase and MMP-1, -2 and -9.
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: 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: 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*; D006877:Hydroxamic Acids / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013386:Succinates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C097658:CGS 27023A; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D013386:Succinates; D013449:Sulfonamides; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein