Author/Authors :
Masahiko Uchida، نويسنده , , Kosuke Okazaki، نويسنده , , Harunobu Mukaiyama، نويسنده , , Hidetoshi Isawa، نويسنده , , Hiroaki Kobayashi، نويسنده , , Hiroaki Shiohara، نويسنده , , Hideyuki Muranaka، نويسنده , , Yuichiro Kai، نويسنده , , Norihiko Kikuchi، نويسنده , , Hideki Takeuchi، نويسنده , , Kenji Yokoyama، نويسنده , , Eiichi Tsuji، نويسنده , , Tomonaga Ozawa، نويسنده , , Yuji Hoyano، نويسنده , , Takashi Koizumi ، نويسنده , , Keiko Misawa، نويسنده , , Kiyoto Hara، نويسنده , , Shigeru Nakano، نويسنده , , Yasuoki Murakami، نويسنده , , Hiroaki Okuno، نويسنده ,
Abstract :
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.
Keywords :
anticoagulant , serine protease inhibitor , factor Xa , prodrug , Amidoxime
