Potent and selective TF/FVIIa inhibitors containing a neutral P1 ligand.
Inhibition of tissue factor/factor VIIa complex (TF/FVIIa) is an attractive strategy for antithrombotic therapies. We began with an investigation of a non-amidine TF/FVIIa inhibitor based on a modification of amidine compound 1. Optimization of the substituents on the P1 phenyl portion of the compound 1 led to a neutral or less basic alternative for the 4-amidinophenyl moiety. By further optimization of the substituents on the central phenyl ring, a highly potent and selective TF/FVIIa inhibitor 17d was discovered.
Miura
Masanori
M
Institute for Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. masannori-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
Kawasaki
Tomihisa
T
Sakamoto
Shuichi
S
Okada
Minoru
M
Ohta
Mitsuaki
M
Tsukamoto
Shin-ichi
S
D000578:Amidines / Q000737:chemistry; D001555:Benzene Derivatives; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D005343:Fibrinolytic Agents / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
D000578:Amidines; D001555:Benzene Derivatives; D005343:Fibrinolytic Agents; D008024:Ligands; D013925:Thromboplastin; D015942:Factor VIIa