Benzene-di-N-octylcarbamates as conformationally constrained phospholipase A(2) inhibitors

Bioorg Med Chem Lett. 2004 Feb 9;14(3):751-5. doi: 10.1016/j.bmcl.2003.11.047.

Abstract

Conformationally constrained 1,2-, 1,3-, and 1,4-benzene-di-N-octylcarbamates are potent reversible competitive inhibitors of Naja mocambique mocambique phospholipase A(2) with the K(i) values of 11, 4, and 15 microM, respectively. With the angle of 120(o) between two C(benzene)-O bonds, 1,3-benzene-di-N-octylcarbamate mimics the preferable eclipsed C(sn-2)-O/C(sn-3)-O conformer of phospholipid in the enzyme-phospholipid complex. Further, a three-step phospholipase A(2) inhibition mechanism by the inhibitor is proposed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Binding, Competitive
  • Carbamates / chemistry*
  • Carbamates / pharmacology*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Molecular Conformation
  • Molecular Structure
  • Pancreas / enzymology*
  • Phospholipases A / antagonists & inhibitors*
  • Phospholipases A / metabolism
  • Phospholipids / metabolism
  • Phosphorylcholine / metabolism
  • Structure-Activity Relationship
  • Swine

Substances

  • Carbamates
  • Enzyme Inhibitors
  • Phospholipids
  • Phosphorylcholine
  • Phospholipases A