title: Orally active factor Xa inhibitors: investigation of a novel series of 3-amidinophenylsulfonamide derivatives using an amidoxime prodrug strategy.
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.
authors.affiliation: Research and Development Division, Kissei Pharmaceutical Co., Ltd, 4365-1 Hotaka-Kashiwabara, Azumino-City, Nagano 399-8304, Japan. masahiko_uchida@pharm.kissei.co.jp
authors.forename: Masahiko
authors.initials: M
authors.lastname: Uchida
authors.forename: Kosuke
authors.initials: K
authors.lastname: Okazaki
authors.forename: Harunobu
authors.initials: H
authors.lastname: Mukaiyama
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Isawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiohara
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Muranaka
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Kai
authors.forename: Norihiko
authors.initials: N
authors.lastname: Kikuchi
authors.forename: Hideki
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tsuji
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ozawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hoyano
authors.forename: Takashi
authors.initials: T
authors.lastname: Koizumi
authors.forename: Keiko
authors.initials: K
authors.lastname: Misawa
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Hara
authors.forename: Shigeru
authors.initials: S
authors.lastname: Nakano
authors.forename: Yasuoki
authors.initials: Y
authors.lastname: Murakami
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okuno
mesh_terms: 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
chemical_list: D000578:Amidines; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D010091:Oximes; D011355:Prodrugs; D013449:Sulfonamides; D014357:Trypsin