Exploring the Effect of Cyclization of Histamine H(1) Receptor Antagonists on Ligand Binding Kinetics

[Image: see text] There is an increasing interest in guiding hit optimization by considering the target binding kinetics of ligands. However, compared to conventional structure–activity relationships, structure–kinetics relationships have not been as thoroughly explored, even for well-studied archetypical drug targets such as the histamine H(1) receptor (H(1)R), a member of the family A G-protein coupled receptor. In this study, we show that the binding kinetics of H(1)R antagonists at the H(1)R is dependent on the cyclicity of both the aromatic head group and the amine moiety of H(1)R ligands, the chemotypes that are characteristic for the first-generation H(1)R antagonists. Fusing the two aromatic rings of H(1)R ligands into one tricyclic aromatic head group prolongs the H(1)R residence time for benchmark H(1)R ligands as well as for tailored synthetic analogues. The effect of constraining the aromatic rings and the basic amines is systematically explored, leading to a coherent series and detailed discussions of structure–kinetics relationships. This study shows that cyclicity has a pronounced effect on the binding kinetics.