Orally active factor Xa inhibitors: investigation of a novel series of 3-amidinophenylsulfonamide derivatives using an amidoxime prodrug strategy.
A series of novel and potent 3-amidinophenylsulfonamide derivatives of factor Xa inhibitors were designed and synthesized using an amidoxime prodrug strategy. We focused on systemic clearance of parent compounds in rats, and performed in vivo pharmacokinetic screening. Incorporation of a carboxymethoxy group markedly improved systemic clearance (compound 43), and the related amidoxime 44 showed sufficient prodrug conversion. Compound 45, the double prodrug of 43, exhibited practicable bioavailability after oral administration in rats. Among the various compounds under investigation, KFA-1982 was selected for clinical development.
Uchida
Masahiko
M
Research and Development Division, Kissei Pharmaceutical Co., Ltd, 4365-1 Hotaka-Kashiwabara, Azumino-City, Nagano 399-8304, Japan. masahiko_uchida@pharm.kissei.co.jp
Okazaki
Kosuke
K
Mukaiyama
Harunobu
H
Isawa
Hidetoshi
H
Kobayashi
Hiroaki
H
Shiohara
Hiroaki
H
Muranaka
Hideyuki
H
Kai
Yuichiro
Y
Kikuchi
Norihiko
N
Takeuchi
Hideki
H
Yokoyama
Kenji
K
Tsuji
Eiichi
E
Ozawa
Tomonaga
T
Hoyano
Yuji
Y
Koizumi
Takashi
T
Misawa
Keiko
K
Hara
Kiyoto
K
Nakano
Shigeru
S
Murakami
Yasuoki
Y
Okuno
Hiroaki
H
D000284:Administration, Oral; D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D006801:Humans; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D010091:Oximes / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D014357:Trypsin / Q000737:chemistry
D000578:Amidines; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D010091:Oximes; D011355:Prodrugs; D013449:Sulfonamides; D014357:Trypsin