title: Design and synthesis of piperazine-based matrix metalloproteinase inhibitors.
abstract: A new generation of cyclic matrix metalloproteinase (MMP) inhibitors derived from dl-piperazinecarboxylic acid has been described. The design involves: incorporation of hydroxamic acid as the bidentate chelating agent for catalytic Zn(2+), placement of a sulfonamide group at the 1N-position of the piperazine ring to fill the S1' pocket of the enzyme, and finally attachment of diverse functional groups at the 4N-position to optimize potency and peroral absorption. A unique combination of all three elements produced inhibitor 20 with high affinity for MMPs 1, 3, 9, and 13 (24, 18, 1.9, and 1.3 nM, respectively). X-ray crystallography data obtained for MMP-3 cocrystallized with 20 gave detailed information on key binding interactions defining an overall scaffold geometry for piperazine-based MMP inhibitors.
authors.affiliation: Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cheng
authors.forename: B
authors.initials: B
authors.lastname: De
authors.forename: S
authors.initials: S
authors.lastname: Pikul
authors.forename: N G
authors.initials: NG
authors.lastname: Almstead
authors.forename: M G
authors.initials: MG
authors.lastname: Natchus
authors.forename: M V
authors.initials: MV
authors.lastname: Anastasio
authors.forename: S J
authors.initials: SJ
authors.lastname: McPhail
authors.forename: C E
authors.initials: CE
authors.lastname: Snider
authors.forename: Y O
authors.initials: YO
authors.lastname: Taiwo
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: C M
authors.initials: CM
authors.lastname: Dunaway
authors.forename: F
authors.initials: F
authors.lastname: Gu
authors.forename: M E
authors.initials: ME
authors.lastname: Dowty
authors.forename: G E
authors.initials: GE
authors.lastname: Mieling
authors.forename: M J
authors.initials: MJ
authors.lastname: Janusz
authors.forename: S
authors.initials: S
authors.lastname: Wang-Weigand
mesh_terms: D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015195:Drug Design; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C404925:N-hydroxy-1-(4-methoxyphenyl)sulfonyl-4-benzyloxycarbonylpiperazine-2-carboxamide; D010879:Piperazines; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D013449:Sulfonamides; D008666:Metalloendopeptidases