Dibasic non-imidazole histamine H3 receptor antagonists with a rigid biphenyl scaffold

A class of rigid, dibasic, non-imidazole H3 antagonists was developed, starting from a series of previously described flexible compounds. The original polymethylene chain between two tertiary amine groups was replaced by a rigid scaffold, composed by a phenyl ring or a biphenyl fragment. Modulation of the distance between the two amine groups, and of their alkyl substituents, was driven by superposition of molecular models and docking into a receptor model, resulting in the identification of 1,1′-[biphenyl-4,4′-diylbis(methylene)]bis-piperidine (5) as a subtype-selective H3 antagonist with high binding affinity (pKi = 9.47) at human H3 histamine receptor.

A class of rigid dibasic H3 antagonists is reported. Compound 5 with subnanomolar affinity for human H3 receptor was identified.Figure optionsDownload as PowerPoint slide