title: Novel strategy to boost oral anticoagulant activity of blood coagulation enzyme inhibitors based on biotransformation into hydrophilic conjugates.
abstract: The blood coagulation cascade represents an attractive target for antithrombotic drug development, and recent studies have attempted to identify oral anticoagulants with inhibitory activity for enzymes in this cascade, with particular attention focused on thrombin and factor Xa (fXa) as typical targets. We previously described the discovery of the orally active fXa inhibitor darexaban (1) and reported a unique profile that compound 1 rapidly transformed into glucuronide YM-222714 (2) after oral administration. Here, we propose a novel strategy towards the discovery of an orally active anticoagulant that is based on the bioconversion of a non-amidine inhibitor into the corresponding conjugate to boost ex vivo anticoagulant activity via an increase in hydrophilicity. Computational molecular modeling was utilized to select a template scaffold and design a substitution point to install a potential functional group for conjugation. This strategy led to the identification of the phenol-derived fXa inhibitor ASP8102 (14), which demonstrated highly potent anticoagulant activity after biotransformation into the corresponding glucuronide (16) via oral dosing.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. Electronic address: tsukasa.ishihara@astellas.com.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ishihara
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Koga
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Mori
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Sugasawa
authors.affiliation: Pharmacovigilance, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Iwatsuki
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Fukushi
authors.initials: F
authors.lastname: Hirayama
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001381:Azepines / Q000737:chemistry / Q000378:metabolism; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D015951:Factor Xa / Q000737:chemistry* / Q000378:metabolism; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism; D006207:Half-Life; D008252:Macaca fascicularis; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011517:Prothrombin Time; D013917:Thrombin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D001381:Azepines; D001549:Benzamides; D004791:Enzyme Inhibitors; D020719:Glucuronides; C570990:darexaban glucuronide; D013917:Thrombin; D015951:Factor Xa
keywords: Anticoagulant; Conjugation; Docking study; Factor Xa