title: Design, synthesis and biological activity of YM-60828 derivatives. Part 2: potent and orally-bioavailable factor Xa inhibitors based on benzothiadiazine-4-one template.
abstract: Compound YM-60828 was previously characterized in our laboratory as a potent, selective and orally-bioavailable Factor Xa (FXa) inhibitor. The L-shape conformation of this compound in the active site of FXa was recognized as an important factor in displaying its FXa inhibitory activity. This led to the exploration of conformationally restricted cyclic scaffolds bearing a similar active conformation. The current study investigated a novel series of benzothiadiazine-4-one based compounds as FXa inhibitors. Structure-activity relationship (SAR) investigations revealed some potent FXa inhibitors that were selected for further in vitro and ex vivo anticoagulant studies. Among them, compound 6j (YM-169920) was proved to be most effective anticoagulant in this series. The synthesis and SAR in addition to docking studies of this class of inhibitors are described.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. hirayaf@yamanouchi.ac.jp
authors.forename: Fukushi
authors.initials: F
authors.lastname: Hirayama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koshio
authors.forename: Naoko
authors.initials: N
authors.lastname: Katayama
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ishihara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kaizawa
authors.forename: Yuta
authors.initials: Y
authors.lastname: Taniuchi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sato
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Sakai-Moritani
authors.forename: Seiji
authors.initials: S
authors.lastname: Kaku
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001581:Benzothiadiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001682:Biological Availability; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011517:Prothrombin Time; D012453:Saimiri; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D001581:Benzothiadiazines; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D010880:Piperidines; D014361:Trypsin Inhibitors; C111032:YM 60828; D013917:Thrombin