Refinement of histamine H3 ligands pharmacophore model leads to a new class of 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.
Roche
Olivier
O
F. Hoffmann-La Roche Ltd., Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland.
Nettekoven
Matthias
M
Vifian
Walter
W
Sarmiento
Rosa Maria Rodriguez
RM
D015195:Drug Design; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013329:Structure-Activity Relationship
D017442:Histamine Agonists; D008024:Ligands; D009281:Naphthalenes; D018100:Receptors, Histamine H3