title: Dibasic (amidinoaryl)propanoic acid derivatives as novel blood coagulation factor Xa inhibitors.
abstract: Since activated factor X (FXa) is a coagulant enzyme that generates thrombin and participates in both intrinsic and extrinsic coagulation pathways, inhibition of FXa may be more effective than inactivation of thrombin for interrupting blood coagulation. To assess the possible effectiveness of FXa inhibition as an anticoagulant, we designed and synthesized 3-(amidinoaryl)-2-[4-[(3S)-3-pyrrolidinyloxy]phenyl]propanoi c acid derivatives as low molecular weight, nonpeptidic, orally active FXa inhibitors. These derivatives exhibited potent and highly selective anti-FXa activity in vitro and anticoagulant activity on oral administration. The most promising compound, (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]- 3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (4,DX-9065a), inhibited 50% of FXa activity (IC50) at 0.07 microM, doubled plasma recalcification time (PRCT) at 0.5 microM, and significantly prolonged activated partial thromboplastin time (APTT) at a dose of 100 mg/kg on oral administration. In contrast with FXa inhibition, 4 showed no activity against thrombin (IC50 > 2000 microM).
authors.affiliation: Research Institute, Daiichi Pharmaceutical Company, Ltd., Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nagahara
authors.forename: Y
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: K
authors.initials: K
authors.lastname: Inamura
authors.forename: S
authors.initials: S
authors.lastname: Katakura
authors.forename: S
authors.initials: S
authors.lastname: Komoriya
authors.forename: H
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: T
authors.initials: T
authors.lastname: Hara
authors.forename: M
authors.initials: M
authors.lastname: Iwamoto
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D002118:Calcium / Q000097:blood; D003198:Computer Simulation; D003460:Crystallization; D065427:Factor Xa Inhibitors; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010314:Partial Thromboplastin Time; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; 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; D002118:Calcium