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cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4(A-987306) is a new histamine H4antagonist. The compound is potent in H4receptor binding assays (rat H4, Ki= 3.4 nM, human H4Ki= 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H4receptors in cell-based FLIPR assays. Compound 4also demonstrated H4antagonism in vivo in mice, blocking H4-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED50of 42 μmol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain. [ABSTRACT FROM AUTHOR]

A series of 2-aminopyrimidines was synthesized as ligands of the histamine H 4receptor (H 4R). 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 NH 2at 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 H 4R antagonists in pain. [ABSTRACT FROM AUTHOR]