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

Bioorg Med Chem Lett. 2008 Aug 1;18(15):4377-9. doi: 10.1016/j.bmcl.2008.06.062. Epub 2008 Jun 21.

Abstract

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.

MeSH terms

  • Drug Design*
  • Histamine Agonists / chemical synthesis*
  • Histamine Agonists / chemistry
  • Histamine Agonists / pharmacology
  • Humans
  • Ligands
  • Models, Biological*
  • Molecular Structure
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology*
  • Receptors, Histamine H3 / drug effects*
  • Structure-Activity Relationship

Substances

  • Histamine Agonists
  • Ligands
  • Naphthalenes
  • Receptors, Histamine H3