title: Novel and highly potent histamine H3 receptor ligands. Part 3: an alcohol function to improve the pharmacokinetic profile.
abstract: Synthesis and biological evaluation of potent histamine H3 receptor antagonists incorporating a hydroxyl function are described. Compounds in this series exhibited nanomolar binding affinities for human receptor, illustrating a new possible component for the H3 pharmacophore. As demonstrated with compound BP1.4160 (cyclohexanol 19), the introduction of an alcohol function counter-intuitively allowed to reach high in vivo efficiency and favorable pharmacokinetic profile with reduced half-life.
authors.affiliation: Bioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint-Grégoire, France. o.labeeuw@bioprojet.com
authors.forename: Olivier
authors.initials: O
authors.lastname: Labeeuw
authors.forename: Nicolas
authors.initials: N
authors.lastname: Levoin
authors.forename: Olivia
authors.initials: O
authors.lastname: Poupardin-Olivier
authors.forename: Thierry
authors.initials: T
authors.lastname: Calmels
authors.forename: Xavier
authors.initials: X
authors.lastname: Ligneau
authors.forename: Isabelle
authors.initials: I
authors.lastname: Berrebi-Bertrand
authors.forename: Philippe
authors.initials: P
authors.lastname: Robert
authors.forename: Jeanne-Marie
authors.initials: JM
authors.lastname: Lecomte
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Schwartz
authors.forename: Marc
authors.initials: M
authors.lastname: Capet
mesh_terms: D000818:Animals; D001665:Binding Sites; D003511:Cyclohexanols / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D054314:Drug Inverse Agonism; D000431:Ethanol / Q000737:chemistry*; D006207:Half-Life; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics
chemical_list: C584238:BP1.4160; D003511:Cyclohexanols; D054828:Histamine H3 Antagonists; D008024:Ligands; D018100:Receptors, Histamine H3; D011994:Recombinant Proteins; D000431:Ethanol