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Structure−Activity Studies on a Series of a 2-Aminopyrimidine-Containing Histamine H4 Receptor Ligands

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Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, and Abbott Bioresearch Center, 100 Research Drive, Worcester, Massachusetts 01605-5314
* To whom correspondence should be addressed. Address: Department R4MN, Building AP9A/2, 100 Abbott Park Road, Abbott Park, Illinois, 60064-6123. E-mail: [email protected]. Phone: 847-935-4194. Fax: 847-937-9195.
†Abbott Laboratories.
‡Abbott Bioresearch Center.
Cite this: J. Med. Chem. 2008, 51, 20, 6571–6580
Publication Date (Web):September 24, 2008
Copyright © 2008 American Chemical Society

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    A series of 2-aminopyrimidines was synthesized as ligands of the histamine H4 receptor (H4R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3, 4-tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylamine. We further studied this compound by systematically modifying the core pyrimidine moiety, the methylpiperazine at position 4, the NH2 at position 2, and positions 5 and 6 of the pyrimidine ring. The pyrimidine 6 position benefited the most from this optimization, especially in analogs in which the 6-tert-butyl was replaced with aromatic and secondary amine moieties. The highlight of the optimization campaign was compound 4, 4-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzonitrile, which was potent in vitro and was active as an anti-inflammatory agent in an animal model and had antinociceptive activity in a pain model, which supports the potential of H4R antagonists in pain.

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