title: Identification of potent orally active factor Xa inhibitors based on conjugation strategy and application of predictable fragment recommender system.
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.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. Electronic address: tsukasa.ishihara@astellas.com.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ishihara
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Koga
authors.affiliation: Pharmacovigilance, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Iwatsuki
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Fukushi
authors.initials: F
authors.lastname: Hirayama
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D015951:Factor Xa / Q000737:chemistry* / Q000378:metabolism; D065427:Factor Xa Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D020719:Glucuronides / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011485:Protein Binding; D011517:Prothrombin Time; D013329:Structure-Activity Relationship
chemical_list: D000925:Anticoagulants; D001549:Benzamides; D065427:Factor Xa Inhibitors; D020719:Glucuronides; C037689:benzamide; D015951:Factor Xa
keywords: Collaborative filtering; Conjugation; Factor Xa; Recommender system