New serine protease inhibitors with leukotriene B4 (LTB4) receptor binding affinity.
A series of new trypsin-like serine protease inhibitors, 1, 2 and 7-23, containing amidinobenzene moiety was found to show potent LTB4-receptor affinity. Among them, compounds 1 and 2 were found to be LTB4 receptor antagonists based on an inhibition assay of human polymorphonuclear neutrophil (PMN) intracellular calcium mobilization induced by LTB4. Compounds 1 and 2, which satisfy the reported structural requirements for good oral activity, are expected to show a balanced dual mode of action, i.e., protease inhibitory activity and LTB4 receptor antagonist activity, in vivo.
Nakayama
Y
Y
Minase Research Institute, Ono Pharmaceutical Co., Ltd, Osaka, Japan.
Senokuchi
K
K
Sakaki
K
K
Kato
M
M
Maruyama
T
T
Miyazaki
T
T
Ito
H
H
Nakai
H
H
Kawamura
M
M
D000578:Amidines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000578:Amidines; D018102:Receptors, Leukotriene B4; D015842:Serine Proteinase Inhibitors; D007975:Leukotriene B4; D002118:Calcium