Structure-based design and synthesis of a series of hydroxamic acids with a quaternary-hydroxy group in P1 as inhibitors of matrix metalloproteinases

I C Jacobson; P G Reddy; Z R Wasserman; K D Hardman; M B Covington; E C Arner; R A Copeland; C P Decicco; R L Magolda

doi:10.1016/s0960-894x(98)00125-5

Structure-based design and synthesis of a series of hydroxamic acids with a quaternary-hydroxy group in P1 as inhibitors of matrix metalloproteinases

Bioorg Med Chem Lett. 1998 Apr 7;8(7):837-42. doi: 10.1016/s0960-894x(98)00125-5.

Authors

I C Jacobson¹, P G Reddy, Z R Wasserman, K D Hardman, M B Covington, E C Arner, R A Copeland, C P Decicco, R L Magolda

Affiliation

¹ DuPont Merck Pharmaceutical Company, Department of Physical and Chemical Science, Wilmington, Delaware, USA.

PMID: 9871551
DOI: 10.1016/s0960-894x(98)00125-5

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.

MeSH terms

Catalytic Domain
Collagenases / chemistry
Computer Simulation
Drug Design
Enzyme Precursors / antagonists & inhibitors
Enzyme Precursors / chemistry
Hydrogen Bonding
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry*
Hydroxamic Acids / pharmacology
Indicators and Reagents
Matrix Metalloproteinase 1
Matrix Metalloproteinase 3 / chemistry
Matrix Metalloproteinase Inhibitors
Metalloendopeptidases / antagonists & inhibitors*
Metalloendopeptidases / chemistry
Models, Molecular
Molecular Conformation
Molecular Structure
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacology
Protein Conformation
Structure-Activity Relationship

Substances

Enzyme Precursors
Hydroxamic Acids
Indicators and Reagents
Matrix Metalloproteinase Inhibitors
Protease Inhibitors
Collagenases
Metalloendopeptidases
prostromelysin
Matrix Metalloproteinase 3
Matrix Metalloproteinase 1