2. Academic Validation
  3. 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

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

  • J Med Chem. 2008 Oct 23;51(20):6547-57. doi: 10.1021/jm800670r.
Marlon D Cowart 1,  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,  Jorge D Brioni
Affiliations

Affiliation

  • 1 Department of Neuroscience Research, Abbott Laboratories, Abbott Park, Illinois 60064-6123, USA. marlon.d.cowart@abbott.com
PMID: 18817367 DOI: 10.1021/jm800670r
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).

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