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.

Graphical abstractAn amidoxime/ester double prodrug 45 demonstrated sufficient oral bioavailability and encouraging oral antithrombotic activity in mice. Among the various compounds under investigation, KFA-1982 was selected for clinical development.Figure optionsDownload full-size imageDownload as PowerPoint slide