Active site-directed plasmin inhibitors: Extension on the P2 residue

Bioorg Med Chem. 2016 Feb 15;24(4):545-53. doi: 10.1016/j.bmc.2015.12.009. Epub 2015 Dec 8.

Abstract

Based on the structure of YO-2 [N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr(O-picolyl)-NH-octyl], active site-directed plasmin (Plm) inhibitors were explored. The picolyl moiety in the Tyr(O-picolyl) residue (namely, the P2 residue) was replaced with smaller or larger groups, such as hydrogen, tert-butyl, benzyl, (2-naphthyl)methyl, and (quinolin-2-yl)methyl. Those efforts produced compound 17 {N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr[O-(quinolin-2-yl)methyl]-NH-octyl} [IC50=0.22 and 77μM for Plm and urokinase (UK), respectively], which showed not only 2.4-fold greater Plm inhibition than YO-2, but also an improvement in selectivity (Plm/UK) by 35-fold. The docking experiments of the Plm-17 complexes disclosed that the amino group of the tranexamyl moiety interacted with the side-chain of Asp753 which formed S1 site.

Keywords: Active site-directed inhibitor; Plasmin inhibitor; Selectivity; Urokinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifibrinolytic Agents / chemical synthesis
  • Antifibrinolytic Agents / chemistry
  • Antifibrinolytic Agents / pharmacology*
  • Catalytic Domain / drug effects
  • Dose-Response Relationship, Drug
  • Fibrinolysin / antagonists & inhibitors*
  • Fibrinolysin / chemistry*
  • Fibrinolysin / metabolism
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Structure-Activity Relationship
  • Tyrosine / antagonists & inhibitors
  • Tyrosine / metabolism
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors
  • Urokinase-Type Plasminogen Activator / metabolism

Substances

  • Antifibrinolytic Agents
  • Tyrosine
  • Fibrinolysin
  • Urokinase-Type Plasminogen Activator