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

A series of trisubstituted pyridines have been prepared that exhibit i n vitro leukotriene B4 (LTB4, 1) receptor antagonist activity. Previou s 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 act ivity up to 10 muM. Subsequent modifications of the lipid tail and ary l head group region led to the discovery of aniline 50 (SB 201146). Th is compound, also free of agonist activity, possesses high affinity fo r the LTB4 receptor (K(i) = 4.7 nM).