Rotationally constrained 2,4-diamino-5,6-disubstituted pyrimidines: a new class of histamine H4 receptor antagonists with improved druglikeness and in vivo efficacy in pain and inflammation models.

A new structural class of histamine H 4 receptor antagonists (6-14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H 4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H 4 antagonists, functional H 4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H 4 pharmacology. It is a potent H 4 antagonist in functional assays across species (FLIPR Ca (2+) flux, K b < 5.7 nM), has high (>190x) selectivity for H 4, and combines good PK in rats and mice (t 1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED 50 = 37 micromol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED 50 = 72 micromol/kg, rat).

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

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.

A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.

Osteoporosis is a complex disease that affects >10 million people in the United States and results in 1.5 million fractures annually. In addition, the high prevalence of osteopenia (low bone mass) in the general population places a large number of people at risk for developing the disease. In an effort to identify genetic factors influencing bone density, we characterized a family that includes individuals who possess exceptionally dense bones but are otherwise phenotypically normal. This high-bone-mass trait (HBM) was originally localized by linkage analysis to chromosome 11q12-13. We refined the interval by extending the pedigree and genotyping additional markers. A systematic search for mutations that segregated with the HBM phenotype uncovered an amino acid change, in a predicted beta-propeller module of the low-density lipoprotein receptor-related protein 5 (LRP5), that results in the HBM phenotype. During analysis of >1,000 individuals, this mutation was observed only in affected individuals from the HBM kindred. By use of in situ hybridization to rat tibia, expression of LRP5 was detected in areas of bone involved in remodeling. Our findings suggest that the HBM mutation confers a unique osteogenic activity in bone remodeling, and this understanding may facilitate the development of novel therapies for the treatment of osteoporosis.