title: Design, synthesis and biological activity of selective and orally available TF/FVIIa complex inhibitors containing non-amidine P1 ligands.
abstract: We found the novel selective and orally available non-amidine TF/FVIIa complex inhibitor 21e, 4-({[(1S)-(aminocarbonyl)-3-methylbutyl]amino}carbonyl)-2'-({[4- (aminomethyl)phenyl]amino}carbonyl)-4'-(methylamino)biphenyl-2- carboxylic acid. The derivatives were synthesized by conversions of the isobutyl moiety and the introduction of alkylamino groups to 4'-position of the central phenyl ring of compounds 2a and 2b reported previously. Some compounds show increased in vitro anti-TF/FVIIa and PT prolongation activities. Among them, compound 21e reached and sustained micromolar plasma concentration levels of up to 2h after oral administration in mice. Moreover, compound 21e did not prolong the bleeding time even at the highest dose level in cynomolgus monkeys, while PT was prolonged 3.7-fold increases at this dose.
authors.affiliation: Institute for Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. masanori-miura@jp.astellas.com
authors.forename: Masanori
authors.initials: M
authors.lastname: Miura
authors.forename: Norio
authors.initials: N
authors.lastname: Seki
authors.forename: Takanori
authors.initials: T
authors.lastname: Koike
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ishihara
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Niimi
authors.forename: Fukushi
authors.initials: F
authors.lastname: Hirayama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shigenaga
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Sakai-Moritani
authors.forename: Ayako
authors.initials: A
authors.lastname: Tagawa
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Minoru
authors.initials: M
authors.lastname: Okada
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019774:Blood Coagulation Factor Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008074:Lipoproteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D008744:Methylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
chemical_list: C517084:4-((((1S)-(aminocarbonyl)-3-methylbutyl)amino)carbonyl)-2'-(((4- (aminomethyl)phenyl)amino)carbonyl)-4'-(methylamino)biphenyl-2- carboxylic acid; D001713:Biphenyl Compounds; D019774:Blood Coagulation Factor Inhibitors; D008024:Ligands; D008074:Lipoproteins; D008744:Methylamines; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin; D015942:Factor VIIa