Synthesis of structural analogues of leukotriene B4 and their receptor binding activity

Article abstract of DOI:10.1016/S0968-0896(97)00090-4

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 μM; 38c, IC₅₀ = 0.020 μM; 52a, IC₅₀ = 0.020 μM; 52b, IC₅₀ = 0.018 μM). 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 μM.