Structure-based design and synthesis of a series of hydroxamic acids with a quaternary-hydroxy group in P1 as inhibitors of matrix metalloproteinases.
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.
Jacobson
I C
IC
DuPont Merck Pharmaceutical Company, Department of Physical and Chemical Science, Wilmington, Delaware, USA.
Reddy
P G
PG
Wasserman
Z R
ZR
Hardman
K D
KD
Covington
M B
MB
Arner
E C
EC
Copeland
R A
RA
Decicco
C P
CP
Magolda
R L
RL
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
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