1,2-dibenzamidobenzene inhibitors of human factor Xa

High-throughput screening of a combinatorial library of diamidophenols yiel ded lead compounds with the ability to inhibit human factor Xa (fXa) at mic romolar concentrations (e.g. compound 4, fXa apparent K-ass = 0.64 x 10(6) L/mol). SAR studies in this novel structural series of fXa inhibitors showe d that the phenolic hydroxyl group was not essential for activity. The best activity was found in substituted 1,2-dibenzamidobenzenes in which the phe nyl group of one benzoyl group (A-ring) was substituted in the 4-position w ith relatively small lipophilic or polarizable groups such as methoxy, viny l, or chloro and the phenyl group of the other benzoyl group (B-ring) was s ubstituted in the 4-position with larger lipophilic groups such as tert-but yl or dimethylamino. The central phenyl ring (C-ring) tolerated a wide vari ety of substituents, but methoxy, methanesulfonamido, hydroxyl, and carboxy l substitution produced slightly higher levels of activity than other subst ituents when present in combination with favorable B-ring substitution. Met hylation of the amide nitrogen atoms was found to greatly decrease activity . Compound 12 is the highest affinity fXa inhibitor in this group of compou nds, having fXa apparent K-ass = 25.5 x 10(6) L/mol, about 40x more active than the original lead. This lead series does not show potent inhibition of human thrombin. A model for the binding of these ligands to the fXa active site is proposed. The model is consistent with the observed SAR and can se rve to guide future SAR studies.