title: Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies.
abstract: The combination of antagonism at histamine H(3) receptor and the stimulation of insulin secretion have been proposed as an approach to new dual therapeutic agents for the treatment of type 2 diabetes mellitus associated with obesity. We have designed and synthesized a new series of non-imidazole derivatives, based on a basic amine ring connected through an alkyl spacer of variable length to a phenoxysulfonylurea moiety. These compounds were initially evaluated for histamine H(3) receptor binding affinities, suggesting that a propoxy chain linker between the amine and the core ring could be essential for optimal binding affinity. Compound 56, 1-(naphthalen-1-yl)-3-[(p-(3-pyrrolidin-1-ylpropoxy)benzene)]sulfonylurea exhibited the best H(3) antagonism affinity. However, since all these derivatives failed to block K(ATP) channels, the link of these two related moieties should not be considered a good pharmacophore for obtaining new dual H(3) antagonists with insulinotropic activity, suggesting the necessity to propose a new chemical hybrid prototype.
authors.affiliation: Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada (CIFA), Universidad de Navarra, c/Irunlarrea, 1, E-31008 Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Ceras
authors.forename: Nuria
authors.initials: N
authors.lastname: Cirauqui
authors.forename: Silvia
authors.initials: S
authors.lastname: Pérez-Silanes
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aldana
authors.forename: Antonio
authors.initials: A
authors.lastname: Monge
authors.forename: Silvia
authors.initials: S
authors.lastname: Galiano
mesh_terms: D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D057809:HEK293 Cells; D006633:Histamine Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology*; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D006633:Histamine Antagonists; D026902:Potassium Channel Blockers; D018100:Receptors, Histamine H3; D013453:Sulfonylurea Compounds