Document Report Card

ID: ALA1140165

Journal: J Med Chem

Title: 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.

Authors: Cowart MD, Altenbach RJ, Liu H, Hsieh GC, Drizin I, Milicic I, Miller TR, Witte DG, Wishart N, Fix-Stenzel SR, McPherson MJ, Adair RM, Wetter JM, Bettencourt BM, Marsh KC, Sullivan JP, Honore P, Esbenshade TA, Brioni JD.

Abstract: 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).

CiteXplore: 18817367

DOI: 10.1021/jm800670r