Synthesis of structural analogues of leukotriene B4 and their receptor binding activity.
Structural analogues of leukotriene B4 (LTB4) were designed based on the plausible conformation of LTB4 (1). Joining C-7-C-9 of the conformer A or B into an aromatic ring system led to the discovery of benzene analogues 2, 4 and 6a. Joining C-4-C-9 of the conformer C or D into an aromatic ring system led to the discovery of analogues 3, 5 and 7. The compounds examined in this study were evaluated as to their inhibition of [3H] LTB4 binding to human neutrophils, and by a secondary intact human neutrophil functional assay for agonist/antagonist activity. The first analogues prepared, compounds 2-7, demonstrated moderate potency in the LTB4 receptor binding assay. The modification of these compounds by the introduction of another substituent into the aromatic ring produced a marked increase in receptor binding (28c, IC50 = 0.020 microM; 38c, IC50 = 0.020 microM; 52a, IC50 = 0.020 microM; 52b, IC50 = 0.018 microM). Most of these structural analogues of LTB4 demonstrated agonist activity. Of the analogues prepared in this study, only compound 57 demonstrated weak LTB4 receptor antagonist activity, at 10 microM.
Konno
M
M
Department of Medicinal Chemistry, Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
Nakae
T
T
Sakuyama
S
S
Nishizaki
M
M
Odagaki
Y
Y
Nakai
H
H
Hamanaka
N
N
D002449:Cell Aggregation / Q000187:drug effects; D006801:Humans; D007975:Leukotriene B4 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000378:metabolism*
D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4