title: Indoline derivatives II: synthesis and factor Xa (FXa) inhibitory activities.
abstract: Factor Xa (FXa) is well known to play a pivotal role in blood coagulation, so FXa inhibitor is a promising drug candidate for prophylaxis and treatment of thromboembolic diseases. In the course of our research, we have found that (R)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7-amidinonaphthalen-2-yl)-1-(ethanesulfonyl)indoline ((R)-1) showed potent FXa inhibitory activity in vitro. However, single oral administation (RS)-1 showed high toxicity in mice. Among newly synthesized compounds, ({(RS)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7-amidinonaphthalen-2-yl)indolin-1-yl}sulfonyl)acetic acid ((RS)-11d) showed more potent FXa inhibitory activity and higher safety than (RS)-1. The R-isoform of compound 11d ((R)-11d) exhibited potent in vitro anticoagulant activity in human and hamster plasma. Orally administered (R)-11d also showed dose-dependent potent anticoagulant activity in hamsters, marmosets and cynomolgus monkeys. Compound (R)-11d with potent anticoagulant activity and high safety is therefore favorable as a novel oral FXa inhibitor.
authors.affiliation: Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Noguchi
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Toyoki
authors.initials: T
authors.lastname: Nishimata
authors.forename: Riki
authors.initials: R
authors.lastname: Goto
authors.forename: Miho
authors.initials: M
authors.lastname: Hayakawa
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Sugidachi
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Ogawa
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Asai
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ozeki
authors.forename: Koichi
authors.initials: K
authors.lastname: Fujimoto
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology*; D002144:Callithrix; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008252:Macaca fascicularis; D051379:Mice; D015394:Molecular Structure
chemical_list: C520694:((RS)-5-(1-(acetimidoyl)piperidin-4-yloxy)-2-((7-amidinonaphthalen-2-yl)indolin-1-yl)sulfonyl)acetic acid; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D007211:Indoles; C057812:indoline