Discovery of imidazo[1,5-c]imidazol-3-ones: weakly basic, orally active factor Xa inhibitors.
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.
Imaeda
Yasuhiro
Y
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Imaeda_Yasuhiro@takeda.co.jp
Kuroita
Takanobu
T
Sakamoto
Hiroki
H
Kawamoto
Tetsuji
T
Tobisu
Mamoru
M
Konishi
Noriko
N
Hiroe
Katsuhiko
K
Kawamura
Masaki
M
Tanaka
Toshimasa
T
Kubo
Keiji
K
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001777:Blood Coagulation / Q000187:drug effects; D065692:Cytochrome P-450 CYP3A Inhibitors; D004435:Eating / Q000187:drug effects; D065427:Factor Xa Inhibitors; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020246:Venous Thrombosis / Q000517:prevention & control
C531071:2-(1-(3-((6-chloronaphthalen-2-yl)sulfonyl)propanoyl)piperidin-4-yl)-5-methyl-1,2-dihydro-3H-imidazo(1,5-c)imidazol-3-one; D000925:Anticoagulants; D065692:Cytochrome P-450 CYP3A Inhibitors; D065427:Factor Xa Inhibitors; D007093:Imidazoles; D013450:Sulfones