title: The discovery of YM-60828: a potent, selective and orally-bioavailable factor Xa inhibitor.
abstract: Since Factor Xa (FXa) is well known to play a central role in thrombosis and hemostasis, inhibition of FXa is an attractive target for antithrombotic strategies. As a part of our investigation of a non-peptide, orally available FXa inhibitor, we found that a series of N-[(7-amidino-2-naphthyl)methyl]aniline derivatives possessed potent and selective inhibitory activities. Structure--activity relationship (SAR) of the substituent (R(1)) on the central aniline moiety suggested that increasing lipophilicity caused a detrimental effect on anticoagulant activity (prothrombin time assay) in plasma. Several compounds bearing a hydrophilic substituent in R(1) showed not only potent FXa inhibitory activities but also high anticoagulant activities. The best compound in this series was sulfamoylacetic acid derivative (YM-60828) which was a potent, selective and orally bioavailable FXa inhibitor and was chosen for clinical development.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. hirayaf@yamanouchi.co.jp
authors.forename: Fukushi
authors.initials: F
authors.lastname: Hirayama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koshio
authors.forename: Naoko
authors.initials: N
authors.lastname: Katayama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Yuta
authors.initials: Y
authors.lastname: Taniuchi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sato
authors.forename: Nami
authors.initials: N
authors.lastname: Hisamichi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Sakai-Moritani
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Isao
authors.initials: I
authors.lastname: Yanagisawa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000990:Antithrombin III / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009281:Naphthalenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011517:Prothrombin Time; D013329:Structure-Activity Relationship
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D010880:Piperidines; C111032:YM 60828; D000990:Antithrombin III