TRISUBSTITUTED PYRIDINE LEUKOTRIENE-B(4) RECEPTOR ANTAGONISTS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS

A series of trisubstituted pyridines have been prepared that exhibit in vitro leukotriene B4 (LTB4, 1) receptor antagonist activity. Previous disubstituted pyridines from these labs showed high affinity for the LTB4 receptor but demonstrated agonist activity in functional assays (e.g., 2, K(i) = 1 nM). Compound 4, the initial lead compound of this new series, showed only modest affinity by comparison (K(i) = 282 nM); however, 4 was a receptor antagonist with no demonstrable agonist activity up to 10 muM. Subsequent modifications of the lipid tail and aryl head group region led to the discovery of aniline 50 (SB 201146). This compound, also free of agonist activity, possesses high affinity for the LTB4 receptor (K(i) = 4.7 nM).