title: Design, synthesis and biological activity of YM-60828 derivatives: potent and orally-bioavailable factor Xa inhibitors based on naphthoanilide and naphthalensulfonanilide templates.
abstract: Factor Xa (FXa) is a serine protease which plays a pivotal role in the coagulation cascade. The inhibition of FXa has received great interest as a potential target for the development of new antithrombotic drug. Herein we describe a series of novel 7-amidino-2-naphthoanilide and 7-amidino-2-naphthalensulfonanilide derivatives which are potent FXa inhibitors. These scaffolds are rigid and are allowed to adopt an L-shape conformation which was estimated as the active conformation based on a docking study of YM-60828 with FXa. Optimization of the side chain at the central aniline nitrogen of 7-amidino-2-naphthoanilide has led to several potent and orally active FXa inhibitors. 5h (YM-169964), the best compound of these series, showed potent FXa inhibitory activity (IC(50)=3.9nM) and effectively prolonged prothrombin time by 9.6-fold ex vivo at an oral dose of 3mg/kg in squirrel monkeys.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. hirayaf@yamanouchi.co.jp
authors.forename: Fukushi
authors.initials: F
authors.lastname: Hirayama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koshio
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ishihara
authors.forename: Susumu
authors.initials: S
authors.lastname: Watanuki
authors.forename: Shunichiro
authors.initials: S
authors.lastname: Hachiya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kaizawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kuramochi
authors.forename: Naoko
authors.initials: N
authors.lastname: Katayama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kurihara
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: 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; D000813:Anilides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D015195:Drug Design; D065427:Factor Xa Inhibitors; D005260:Female; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011517:Prothrombin Time; D012453:Saimiri; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D010880:Piperidines; D015842:Serine Proteinase Inhibitors; C111032:YM 60828