title: Discovery of R-142086 as a factor Xa (FXa) inhibitor: syntheses and structure-activity relationships of cinnamyl derivatives.
abstract: To develop a novel and effective anticoagulant with potent and selective factor Xa (FXa) inhibitory activity, a new series of cinnamyl derivatives with enhanced lipophilicity and prodrug forms were synthesized and their biological activities were evaluated. As a result, we found that cinnamyl derivative (N-[4-[1-(acetimidoyl)piperidin-4-yloxy]-3-carbamoylphenyl]-N-[(Z)-3-(3-amidinophenyl)-2-fluoro-2-propenyl]sulfamoyl)acetic acid dihydrochloride (26d, R-142086) with a fluorine atom on the double bond exhibited potent anticoagulant activity and no mutagenic potential. Moreover, orally administered R-142086 exhibited potent anti-FXa activity and anticoagulant activity in dogs.
authors.affiliation: R&D Division, Daiichi 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: Yoichi
authors.initials: Y
authors.lastname: Niitsu
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Asai
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ishizuka
authors.forename: Koichi
authors.initials: K
authors.lastname: Fujimoto
mesh_terms: D000284:Administration, Oral; D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000990:Antithrombin III / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002934:Cinnamates / Q000737:chemistry*; D006224:Cricetinae; D004285:Dogs; D065427:Factor Xa Inhibitors; D006801:Humans; D008297:Male; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000578:Amidines; D000925:Anticoagulants; D002934:Cinnamates; D065427:Factor Xa Inhibitors; C539584:N-(4-(1-(acetimidoyl)piperidin-4-yloxy)-3-carbamoylphenyl)-N-(3-(3-amidinophenyl)-2-fluoro-2-propenyl)sulfamoylacetic acid; D013449:Sulfonamides; D000990:Antithrombin III