Orally active factor Xa inhibitors: investigation of a novel series of 3-amidinophenylsulfonamide derivatives using an amidoxime prodrug strategy

  • Bioorg Med Chem Lett. 2008 Aug 15;18(16):4682-7. doi: 10.1016/j.bmcl.2008.07.009.
Masahiko Uchida  1 ,  Kosuke Okazaki ,  Harunobu Mukaiyama ,  Hidetoshi Isawa ,  Hiroaki Kobayashi ,  Hiroaki Shiohara ,  Hideyuki Muranaka ,  Yuichiro Kai ,  Norihiko Kikuchi ,  Hideki Takeuchi ,  Kenji Yokoyama ,  Eiichi Tsuji ,  Tomonaga Ozawa ,  Yuji Hoyano ,  Takashi Koizumi ,  Keiko Misawa ,  Kiyoto Hara ,  Shigeru Nakano ,  Yasuoki Murakami ,  Hiroaki Okuno
Affiliations
  • 1. Research and Development Division, Kissei Pharmaceutical Co., Ltd, 4365-1 Hotaka-Kashiwabara, Azumino-City, Nagano 399-8304, Japan. [email protected]
PMID: 18667303 DOI: 10.1016/j.bmcl.2008.07.009
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.

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