Design of potent non-thiourea H3-receptor histamine antagonists

Article abstract of DOI:10.1021/jm00017a018

Starting from thioperamide, the first potent and selective H₃-receptor histamine antagonist, analogues have been synthesized and tested in vitro on rat cerebral cortex to explore structure-activity relationships. The aim has been to design potent compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. In a short series of open chain thiourea analogues, the optimum chain length for H₃- antagonist potency was found to be (CH₂)₃. Compounds derived from histamine and possessing an aromatic nitrogen-containing heterocycle on the side chain amino group in place of thiourea show H₃-antagonist activity. Furthermore, when the heterocycle is 2-pyridyl, electron-withdrawing substituents (e.g. NO₂, CF₃, CO₂Me) in the pyridine 5-position increased potency. The synthesis of 4-[4(5)-imidazolyl]piperidine and its conversion into the (trifluoromethyl)pyridyl analogue 5b of thioperamide is described; however, 5b is not as potent as thioperamide. Replacing imidazole by pyridine or substituting imidazole on the remote N considerably reduced potency. Replacing the side-chain NH by S increased potency still further and the most potent compound is 2-{[2-[4(5)-imidazolyl]ethyl]thio}-5-nitropyridine (UCL 1199) which has K(i) = 4.8 nM.