Design of potent non-thiourea H3-receptor histamine antagonists.
J Med Chem
; 38(17): 3342-50, 1995 Aug 18.
Article
em En
| MEDLINE
| ID: mdl-7650687
ABSTRACT
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antagonistas dos Receptores Histamínicos
Limite:
Animals
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
1995
Tipo de documento:
Article
País de afiliação:
Reino Unido