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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 

Design of potent non-thiourea H3-receptor histamine antagonists.

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 Ki = 4.8 nM.[1]

References

  1. Design of potent non-thiourea H3-receptor histamine antagonists. Ganellin, C.R., Hosseini, S.K., Khalaf, Y.S., Tertiuk, W., Arrang, J.M., Garbarg, M., Ligneau, X., Schwartz, J.C. J. Med. Chem. (1995) [Pubmed]
 
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