Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

The combination of antagonism at histamine H3 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 H3 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 H3 antagonism affinity. However, since all these derivatives failed to block KATP channels, the link of these two related moieties should not be considered a good pharmacophore for obtaining new dual H3 antagonists with insulinotropic activity, suggesting the necessity to propose a new chemical hybrid prototype.

Forty-four new sulfonylurea derivatives were designed and synthesized as an approach to finding new dual therapeutic agents for the treatment of type 2 diabetes associated with obesity. Preliminary SAR was performed. Figure optionsDownload as PowerPoint slideHighlights
► Novel sulfonylurea as a promising H3 antagonist.
► New non-imidazoles: a basic amine linked via an alkyl spacer to a phenoxysulfonylurea.
► A propoxy chain between the amine and the core ring is essential for H3 affinity.
► New sulfonylureas designed combining H3 and anti-diabetic pharmacophore elements.