Refinement of histamine H3 ligands pharmacophore model leads to a new class of potent and selective naphthalene inverse agonists

The refined histamine H3 ligand pharmacophore model guided successfully the selection process towards the identification of new, potent and selective naphthalene inverse agonists. The refinement of our original five point pharmacophore model for the H 3 receptor with the addition of a new acceptor feature is presented. The importance of this new acceptor feature for the binding and the selectivity against H 1, H 2 and H 4 has been validated using a newly synthesized naphthalene series. With the SAR deduced from several hundred naphthalene derivatives in various sub-classes the specific role of each pharmacophoric feature, by varying the geometry, size and charge of the molecules, was elucidated. This led to the discovery of a highly potent and selective new compounds series.