title: Structure-based design and synthesis of a series of hydroxamic acids with a quaternary-hydroxy group in P1 as inhibitors of matrix metalloproteinases.
abstract: Examination of the S1 area of the active site of pro-stromelysin has led us to the design of novel and potent inhibitors of matrix metalloproteinases containing constrained quaternary-hydroxy group at P1. The synthesis and biological activity of these compounds with variations at P1', P2', and P3' will be described.
authors.affiliation: DuPont Merck Pharmaceutical Company, Department of Physical and Chemical Science, Wilmington, Delaware, USA.
authors.forename: I C
authors.initials: IC
authors.lastname: Jacobson
authors.forename: P G
authors.initials: PG
authors.lastname: Reddy
authors.forename: Z R
authors.initials: ZR
authors.lastname: Wasserman
authors.forename: K D
authors.initials: KD
authors.lastname: Hardman
authors.forename: M B
authors.initials: MB
authors.lastname: Covington
authors.forename: E C
authors.initials: EC
authors.lastname: Arner
authors.forename: R A
authors.initials: RA
authors.lastname: Copeland
authors.forename: C P
authors.initials: CP
authors.lastname: Decicco
authors.forename: R L
authors.initials: RL
authors.lastname: Magolda
mesh_terms: D020134:Catalytic Domain; D017364:Collagenases / Q000737:chemistry; D003198:Computer Simulation; D015195:Drug Design; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000737:chemistry; D006860:Hydrogen Bonding; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007202:Indicators and Reagents; D020781:Matrix Metalloproteinase 1; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D004792:Enzyme Precursors; D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D017364:Collagenases; D008666:Metalloendopeptidases; C048047:prostromelysin; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1