Stereoselective synthesis and biological evaluation of 3,4-diaminocyclohexanecarboxylic acid derivatives as factor Xa inhibitors

Bioorg Med Chem Lett. 2008 Aug 15;18(16):4587-92. doi: 10.1016/j.bmcl.2008.07.031. Epub 2008 Jul 15.

Abstract

There have been few reports on synthetic methods for cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives 2-5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid 2a and amide 2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.

MeSH terms

  • Animals
  • Anticoagulants / pharmacology
  • Antithrombin III / chemistry
  • Antithrombin III / pharmacology
  • Benzothiazoles / chemical synthesis*
  • Benzothiazoles / pharmacology
  • Blood Coagulation / drug effects
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology*
  • Chemistry, Pharmaceutical / methods
  • Cyclohexanes / chemistry
  • Cyclohexylamines / chemical synthesis*
  • Cyclohexylamines / pharmacology
  • Drug Design
  • Factor Xa / chemistry
  • Factor Xa Inhibitors*
  • Inhibitory Concentration 50
  • Models, Chemical
  • Serine Proteinase Inhibitors / chemical synthesis
  • Stereoisomerism
  • Time Factors

Substances

  • Anticoagulants
  • Benzothiazoles
  • Carboxylic Acids
  • Cyclohexanes
  • Cyclohexylamines
  • Factor Xa Inhibitors
  • Serine Proteinase Inhibitors
  • Cyclohexane
  • Antithrombin III
  • Factor Xa