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 Ca2+ 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 (ED50 = 37 mu mol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED50 = 72 mu mol/kg, rat).