1. Identification of potent orally active factor Xa inhibitors based on conjugation strategy and application of predictable fragment recommender system.
- Author
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Ishihara T, Koga Y, Iwatsuki Y, and Hirayama F
- Subjects
- Administration, Oral, Animals, Anticoagulants chemical synthesis, Anticoagulants metabolism, Benzamides chemical synthesis, Benzamides chemistry, Benzamides metabolism, Drug Design, Factor Xa metabolism, Factor Xa Inhibitors chemical synthesis, Factor Xa Inhibitors metabolism, Glucuronides chemistry, Humans, Male, Mice, Mice, Inbred ICR, Protein Binding, Prothrombin Time, Structure-Activity Relationship, Anticoagulants chemistry, Factor Xa chemistry, Factor Xa Inhibitors chemistry
- 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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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