Synthesis and biological evaluation of the metabolites of 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.
We have recently discovered imidazo[1,5-c]imidazol-3-one derivative 1 as a potent, selective, and orally bioavailable factor Xa (FXa) inhibitor. In this study, we have synthesized metabolites of 1 and evaluated their biological activities. As a result, we identified the active metabolites S-5 and 6 with a potent FXa inhibitory activity comparable to 1 and a favorable pharmacokinetic profile in monkeys.
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Fujimoto_Takuya@takeda.co.jp
Takuya
T
Fujimoto
Mamoru
M
Tobisu
Noriko
N
Konishi
Masaki
M
Kawamura
Norio
N
Tada
Terufumi
T
Takagi
Keiji
K
Kubo
D000818:Animals; D000925:Anticoagulants / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D015951:Factor Xa / Q000502:physiology*; D065427:Factor Xa Inhibitors; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010880:Piperidines / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013055:Spectrophotometry, Infrared
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D007093:Imidazoles; D010880:Piperidines; D015951:Factor Xa