Document Report Card

ID: ALA1140148

Journal: J Med Chem

Title: Structure-activity studies on a series of a 2-aminopyrimidine-containing histamine H4 receptor ligands.

Authors: Altenbach RJ, Adair RM, Bettencourt BM, Black LA, Fix-Stenzel SR, Gopalakrishnan SM, Hsieh GC, Liu H, Marsh KC, McPherson MJ, Milicic I, Miller TR, Vortherms TA, Warrior U, Wetter JM, Wishart N, Witte DG, Honore P, Esbenshade TA, Hancock AA, Brioni JD, Cowart MD.

Abstract: 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 H 4R antagonists in pain.

CiteXplore: 18811133

DOI: 10.1021/jm8005959