A new class of histamine H3 receptor antagonists derived from ligand based design

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 13; pp. 3670 - 3675
• Main Authors: Roche, Olivier, Rodríguez Sarmiento, Rosa María
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01.07.2007
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Chemistry, Pharmaceutical - methods; Drug Design; Drug Evaluation, Preclinical; Histamine Antagonists - chemistry; Humans; Kinetics; Ligands; Medical sciences; Miscellaneous; Models, Chemical; Molecular Conformation; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Protein Binding; Rats; Receptors, Histamine H3 - chemistry; Human; H3 histamine receptor; Cyclohexane derivatives; Rat; Nitrogen heterocycle; SAR; Histamine H3 receptor; Rodentia; Aminoether; Selectivity; Skelgen; De novo design; Vertebrata; Mammalia; Structure activity relation; Inverse agonist; Animal; Piperidine derivatives; Tertiary amine; Bicyclic compound; Affinity; Aromatic compound; Chemical synthesis; Pharmacophore model
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2007.04.056

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.