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.