Indoline derivatives I: synthesis and factor Xa (FXa) inhibitory activities.
A series of bisamidine derivatives each having a ring structure in the center of the molecule was synthesized and their Factor Xa (FXa) inhibitory activities were evaluated. Among them, some indoline derivatives showed potent inhibitory activities in vitro. In particular, (R)-18a having an (R)-configuration at the 2-position of the indoline ring exhibited the most potent FXa inhibitory activity in vitro, more potent than DX-9065a. Furthermore, (R)-18a exhibited more potent anticoagulant activity than DX-9065a. We also succeeded in obtaining an X-ray crystal structure of FXa bound with (R)-18a.
Noguchi
Tetsuji
T
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd, Tokyo, Japan.
Tanaka
Naoki
N
Nishimata
Toyoki
T
Goto
Riki
R
Hayakawa
Miho
M
Sugidachi
Atsuhiro
A
Ogawa
Taketoshi
T
Asai
Fumitoshi
F
Matsui
Yumi
Y
Fujimoto
Koichi
K
D000328:Adult; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D018360:Crystallography, X-Ray; D065427:Factor Xa Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D065427:Factor Xa Inhibitors; D007202:Indicators and Reagents; D007211:Indoles; C057812:indoline