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Eur J Med Chem. 2009 Nov;44(11):4413-25. doi: 10.1016/j.ejmech.2009.06.007. Epub 2009 Jun 16.

Heterocyclic replacement of the central phenyl core of diamine-based histamine H3 receptor antagonists.

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Johnson & Johnson Pharmaceutical Research and Development, LLC, San Diego, CA 92121, United States.


A series of small molecules consisting of a heterocyclic core flanked by two basic functionalities were synthesized and screened for in vitro affinity at the human histamine H(3) receptor (hH(3)R). Nine of the twenty-eight compounds tested were found to possess a hH(3)R K(i) of less than 5 nM and consisted of a diverse range of central hetero-aromatic linkers (pyridine, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, and pyrrole). One member of this series, (4-isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone (37), was found to be a high affinity, selective antagonist that crosses the blood-brain barrier and occupies H(3) receptors after oral administration in the rat.

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