Identification of potent orally active factor Xa inhibitors based on conjugation strategy and application of predictable fragment recommender system

Bioorg Med Chem. 2015 Jan 15;23(2):277-89. doi: 10.1016/j.bmc.2014.11.042. Epub 2014 Dec 5.

Abstract

Anticoagulant agents have emerged as a promising class of therapeutic drugs for the treatment and prevention of arterial and venous thrombosis. We investigated a series of novel orally active factor Xa inhibitors designed using our previously reported conjugation strategy to boost oral anticoagulant effect. Structural optimization of anthranilamide derivative 3 as a lead compound with installation of phenolic hydroxyl group and extensive exploration of the P1 binding element led to the identification of 5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}benzamide (33, AS1468240) as a potent factor Xa inhibitor with significant oral anticoagulant activity. We also reported a newly developed Free-Wilson-like fragment recommender system based on the integration of R-group decomposition with collaborative filtering for the structural optimization process.

Keywords: Collaborative filtering; Conjugation; Factor Xa; Recommender system.

MeSH terms

  • Administration, Oral
  • Animals
  • Anticoagulants / chemical synthesis
  • Anticoagulants / chemistry*
  • Anticoagulants / metabolism
  • Benzamides / chemical synthesis
  • Benzamides / chemistry
  • Benzamides / metabolism
  • Drug Design
  • Factor Xa / chemistry*
  • Factor Xa / metabolism
  • Factor Xa Inhibitors / chemical synthesis
  • Factor Xa Inhibitors / chemistry*
  • Factor Xa Inhibitors / metabolism
  • Glucuronides / chemistry
  • Humans
  • Male
  • Mice
  • Mice, Inbred ICR
  • Protein Binding
  • Prothrombin Time
  • Structure-Activity Relationship

Substances

  • Anticoagulants
  • Benzamides
  • Factor Xa Inhibitors
  • Glucuronides
  • benzamide
  • Factor Xa