| 18507371 |
Imaeda Y, Kuroita T, Sakamoto H, Kawamoto T, Tobisu M, Konishi N, Hiroe K, Kawamura M, Tanaka T, Kubo K: Discovery of imidazo [1,5-c] imidazol-3-ones: weakly basic, orally active factor Xa inhibitors. J Med Chem. 2008 Jun 26;51(12):3422-36. Epub 2008 May 29.
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. |
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