Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part I: exploration of 5-6 fused rings as alternative S1 moieties

Bioorg Med Chem. 2009 Dec 15;17(24):8206-20. doi: 10.1016/j.bmc.2009.10.023. Epub 2009 Oct 31.

Abstract

A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure-activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds.

MeSH terms

  • Administration, Oral
  • Anticoagulants / therapeutic use*
  • Antithrombin III / therapeutic use*
  • Binding Sites
  • Binding, Competitive
  • Crystallography, X-Ray
  • Cyclohexylamines / therapeutic use*
  • Drug Design*
  • Humans
  • Inhibitory Concentration 50
  • Intestinal Absorption / drug effects
  • Kinetics
  • Molecular Structure
  • Platelet Membrane Glycoproteins
  • Protein Conformation
  • Structure-Activity Relationship

Substances

  • Anticoagulants
  • Cyclohexylamines
  • Platelet Membrane Glycoproteins
  • factor X receptors
  • Antithrombin III
  • 1,2-cyclohexanediamine