Design, synthesis and biological activity of selective and orally available TF/FVIIa complex inhibitors containing non-amidine P1 ligands.
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.
Miura
Masanori
M
Institute for Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. masanori-miura@jp.astellas.com
Seki
Norio
N
Koike
Takanori
T
Ishihara
Tsukasa
T
Niimi
Tatsuya
T
Hirayama
Fukushi
F
Shigenaga
Takeshi
T
Sakai-Moritani
Yumiko
Y
Tagawa
Ayako
A
Kawasaki
Tomihisa
T
Sakamoto
Shuichi
S
Okada
Minoru
M
Ohta
Mitsuaki
M
Tsukamoto
Shin-Ichi
S
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*
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