Marlon D. Cowart, Robert J. Altenbach, Huaqing Liu, Gin C. Hsieh, Irene Drizin, Ivan Milicic, Thomas R. Miller, David G. Witte, Neil Wishart, Shannon R. Fix-Stenzel, Michael J. McPherson, Ronald M. Adair, Jill M. Wetter, Brian M. Bettencourt, Kennan C. Marsh, James P. Sullivan, Prisca Honore, Timothy A. Esbenshade, and Jorge D. Brioni
A new structural class of histamine H 4receptor antagonists ( 6− 14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H 4antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H 4antagonists, functional H 4antagonism 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 4pharmacology. It is a potent H 4antagonist in functional assays across species (FLIPR Ca 2+flux, Kb< 5.7 nM), has high (>190×) selectivity for H 4, and combines good PK in rats and mice ( t1/2of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED 50= 37 μmol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED 50= 72 μmol/kg, rat). [ABSTRACT FROM AUTHOR]