Discovery of Imidazo[1,5-c]imidazol-3-ones: Weakly Basic, Orally Active Factor Xa Inhibitors

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• 作者：Yasuhiro Imaeda ; Takanobu Kuroita ; Hiroki Sakamoto ; Tetsuji Kawamoto ; Mamoru Tobisu ; Noriko Konishi ; Katsuhiko Hiroe ; Masaki Kawamura ; Toshimasa Tanaka ; Keiji Kubo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：June 26, 2008
• 年：2008
• 卷：51
• 期：12
• 页码：3422 - 3436
• 全文大小：993K
• 年卷期：v.51,no.12(June 26, 2008)
• ISSN：1520-4804

文摘

The coagulation enzyme factor Xa (FXa) has been recognized as a promising target for the development of new antithrombotic agents. We previously found compound 1 to be an orally bioavailable FXa inhibitor in fasted monkeys; however, 1 showed poor bioavailability in rats and fed monkeys. To work out the pharmacokinetic problems, we focused our synthetic efforts on the chemical conversion of the 4-(imidazo[1,2-a]pyridin-5-yl)piperazine moiety of 1 to imidazolylpiperidine derivatives (fused and nonfused), which resulted in the discovery of the weakly basic imidazo[1,5-c]imidazol-3-one 3q as a potent and selective FXa inhibitor. Compound 3q showed favorable oral bioavailability in rats and monkeys under both fasted and fed conditions and antithrombotic efficacy in a rat model of venous thrombosis after oral administration, without a significant increase in bleeding time (unlike warfarin). On the basis of these promising properties, compound 3q was selected for further evaluation.