Orally active factor Xa inhibitor: synthesis and biological activity of masked amidines as prodrugs of novel 1,4-diazepane derivatives.
Factor Xa (fXa) is a serine protease, which plays a pivotal role in the coagulation cascade. To improve the oral anticoagulant activity of fXa inhibitors containing a 1,4-diazepane moiety as the P4 part, a prodrug strategy was examined. Among the compounds evaluated in this study, amidoxime prodrugs bearing an ester moiety, such as compounds 21 and 30, showed effective oral anticoagulant activity in mice.
Koshio
Hiroyuki
H
Chemistry Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. koshio@yamanouchi.co.jp
Hirayama
Fukushi
F
Ishihara
Tsukasa
T
Kaizawa
Hiroyuki
H
Shigenaga
Takeshi
T
Taniuchi
Yuta
Y
Sato
Kazuo
K
Moritani
Yumiko
Y
Iwatsuki
Yoshiyuki
Y
Uemura
Toshio
T
Kaku
Seiji
S
Kawasaki
Tomihisa
T
Matsumoto
Yuzo
Y
Sakamoto
Shuichi
S
Tsukamoto
Shin-ichi
S
D000284:Administration, Oral; D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000990:Antithrombin III / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001780:Blood Coagulation Tests; D005260:Female; D006801:Humans; D051379:Mice; D011247:Pregnancy; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*
D000578:Amidines; D000925:Anticoagulants; D001372:Aza Compounds; D011355:Prodrugs; D000990:Antithrombin III