SYNTHESIS OF STRUCTURAL ANALOGS OF LEUKOTRIENE B-4 AND THEIR RECEPTOR-BINDING ACTIVITY

Structural analogues of leukotriene B-4 (LTB4) were designed based on the plausible conformation of LTB4 (1). Joining C-7-C-9 of the conform er 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 a n aromatic ring system led to the discovery of analogues 3, 5 and 7. T he compounds examined in this study were evaluated as to their inhibit ion of [H-3] LTB4 binding to human neutrophils, and by a secondary int act human neutrophil functional assay for agonist/antagonist activity. The first analogues prepared, compounds 2-7, demonstrated moderate po tency in the LTB4 receptor binding assay. The modification of these co mpounds by the introduction of another substituent into the aromatic r ing produced a marked increase in receptor binding (28c, IC50 = 0.020 mu M; 38c, IC50 = 0.020 mu M; 52a, IC50 = 0.020 mu M; 52b, IC50 = 0.01 8 mu M). Most of these structural analogues of LTB4 demonstrated agoni st activity. Of the analogues prepared in this study, only compound 57 demonstrated weak LTB4 receptor antagonist activity, at 10 mu M. (C) 1997 Elsevier Science Ltd.