4-Heterocyclohexanone-based inhibitors of the serine protease plasmin

J Med Chem. 1999 Jul 29;42(15):2969-76. doi: 10.1021/jm990110k.

Abstract

Three inhibitors that are based upon a 4-heterocyclohexanone nucleus were synthesized and evaluated for activity against the serine protease plasmin. Inhibitors of plasmin have potential as cancer chemotherapeutic agents that act by blocking both angiogenesis and metastasis. Inhibitor 1 has moderate activity against plasmin but shows good selectivity for this enzyme compared to other serine proteases including trypsin, thrombin, and kallikrein. Inhibitor 2 shows both good activity and selectivity for plasmin. Inhibitor 3, which does not incorporate an aminohexyl group that can interact with the S1 subsite, has poor activity. These results, along with previous work, demonstrate that the 4-heterocyclohexanone nucleus can effectively serve as the basis for designing inhibitors of both serine and cysteine proteases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Cyclohexanes / chemical synthesis*
  • Cyclohexanes / chemistry
  • Fibrinolysin / antagonists & inhibitors*
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / chemistry
  • Structure-Activity Relationship

Substances

  • Cyclohexanes
  • Serine Proteinase Inhibitors
  • Fibrinolysin