A new class of histamine H3 receptor antagonists derived from ligand based design.
Design and synthesis of highly potent and selective non-imidazole inverse agonists for the histamine H(3) receptor is described. The study validates a new pharmacophore model based on the merging of two previously described models. It also demonstrates that the removal of the basic center potentially interacting with ASP3.32 and common to both models leads to loss of activity, whereas the replacement of the second basic center by an acceptor retains the potency.
Roche
Olivier
O
F. Hoffmann-La Roche Ltd, Pharmaceutical Research Basel, Discovery Chemistry, CH-4070 Basel, Switzerland.
Rodríguez Sarmiento
Rosa María
RM
D000818:Animals; D001667:Binding, Competitive; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006633:Histamine Antagonists / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D011485:Protein Binding; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry*
D006633:Histamine Antagonists; D008024:Ligands; D018100:Receptors, Histamine H3