title: Potent and selective TF/FVIIa inhibitors containing a neutral P1 ligand.
abstract: 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.
authors.affiliation: Institute for Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. masannori-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: 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: 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*
chemical_list: D000578:Amidines; D001555:Benzene Derivatives; D005343:Fibrinolytic Agents; D008024:Ligands; D013925:Thromboplastin; D015942:Factor VIIa