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.
Ganellin
C R
CR
Department of Chemistry, Christopher Ingold Laboratories, University College London, UK.
Hosseini
S K
SK
Khalaf
Y S
YS
Tertiuk
W
W
Arrang
J M
JM
Garbarg
M
M
Ligneau
X
X
Schwartz
J C
JC
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects; D015195:Drug Design; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D051381:Rats; D013574:Synaptosomes / Q000187:drug effects; D013890:Thiourea / Q000494:pharmacology
D006633:Histamine Antagonists; D013890:Thiourea