title: Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors.
abstract: The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine-based matrix metalloproteinase (MMP) inhibitors are described. The thiazine- and thiazepine-based inhibitors were discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potent series of inhibitors was obtained by modification of the amino acid D-penicillamine. This amino acid provides a gem-dimethyl group on the thiazine or thiazepine ring which has a dramatic effect on the in vitro potency of this series. In particular, the sulfide 4a and the sulfone 5a were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s against MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel thiazepine-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 4a.
authors.affiliation: Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA.
authors.forename: N G
authors.initials: NG
authors.lastname: Almstead
authors.forename: R S
authors.initials: RS
authors.lastname: Bradley
authors.forename: S
authors.initials: S
authors.lastname: Pikul
authors.forename: B
authors.initials: B
authors.lastname: De
authors.forename: M G
authors.initials: MG
authors.lastname: Natchus
authors.forename: Y O
authors.initials: YO
authors.lastname: Taiwo
authors.forename: F
authors.initials: F
authors.lastname: Gu
authors.forename: L E
authors.initials: LE
authors.lastname: Williams
authors.forename: B A
authors.initials: BA
authors.lastname: Hynd
authors.forename: M J
authors.initials: MJ
authors.lastname: Janusz
authors.forename: C M
authors.initials: CM
authors.lastname: Dunaway
authors.forename: G E
authors.initials: GE
authors.lastname: Mieling
mesh_terms: D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis* / Q000737:chemistry; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; C401383:N-hydroxy-4-((4--methoxyphenyl)sulfonyl)-2,2-dimethylhexahydro-1,4-thiazepine-3-carboxamide 1,1-dioxide; C401382:N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2,2-dimethylhexahydro-1,4-thiazepine-3-carboxamide; D013841:Thiazepines; D013843:Thiazines; D008666:Metalloendopeptidases