title: Design, synthesis and biological activity of amidinobicyclic compounds (derivatives of DX-9065a) as factor Xa inhibitors: SAR study of S1 and aryl binding sites.
abstract: Since factor Xa (fXa) plays a pivotal role in the blood coagulation cascade, inhibition of fXa is thought to be an effective treatment for a variety of thrombotic events. (2S)-2-[4-[[(3S)-1-Acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (DX-9065a) was previously found in our laboratory as a novel orally active factor Xa inhibitor. DX-9065a exhibits a strong inhibitory activity toward fXa by occupying the substrate recognition (called S1) sites and aryl binding sites of fXa. Herein we describe conversions of the amidinonaphthalene and the acetimidoylpyrrolidine moieties of DX-9065a. Some compounds showed remarkably increased in vitro anti-factor Xa and PRCT activities compared with those of DX-9065a. The most promising compound 38 showed four times the prolongation of APTT against DX-9065a after oral administration to rats.
authors.affiliation: Tokyo R&D Center, Daiichi Pharmaceutical Co. Ltd, 16-13, Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan. komor0ni@daiichipharm.co.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Komoriya
authors.forename: Naoaki
authors.initials: N
authors.lastname: Kanaya
authors.forename: Takayasu
authors.initials: T
authors.lastname: Nagahara
authors.forename: Asako
authors.initials: A
authors.lastname: Yokoyama
authors.forename: Kazue
authors.initials: K
authors.lastname: Inamura
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Katakura
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hara
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D065427:Factor Xa Inhibitors; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship
chemical_list: C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D011422:Propionates