Design, synthesis and biological activity of YM-60828 derivatives: potent and orally-bioavailable factor Xa inhibitors based on naphthoanilide and naphthalensulfonanilide templates.
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.
Hirayama
Fukushi
F
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. hirayaf@yamanouchi.co.jp
Koshio
Hiroyuki
H
Ishihara
Tsukasa
T
Watanuki
Susumu
S
Hachiya
Shunichiro
S
Kaizawa
Hiroyuki
H
Kuramochi
Takahiro
T
Katayama
Naoko
N
Kurihara
Hiroyuki
H
Taniuchi
Yuta
Y
Sato
Kazuo
K
Sakai-Moritani
Yumiko
Y
Kaku
Seiji
S
Kawasaki
Tomihisa
T
Matsumoto
Yuzo
Y
Sakamoto
Shuichi
S
Tsukamoto
Shin-ichi
S
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
D000813:Anilides; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D010880:Piperidines; D015842:Serine Proteinase Inhibitors; C111032:YM 60828