The Discovery of Phthalazinone-Based Human H1 and H3 Single-Ligand Antagonists Suitable for Intranasal Administration for the Treatment of Allergic Rhinitis

J Med Chem. 2011 Apr 14;54(7):2183-95. doi: 10.1021/jm1013874. Epub 2011 Mar 7.


A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current antihistamines. Two analogues (56a and 56b) had slightly lower H(1) potency (pA(2) 9.1 and 8.9, respectively, vs 9.7 for the clinical gold-standard azelastine, and H(3) potency (pK(i) 9.6 and 9.5, respectively, vs 6.8 for azelastine). Compound 56a had longer duration of action than azelastine, low brain penetration, and low oral bioavailability, which coupled with the predicted low clinical dose, should limit the potential of engaging CNS-related side-effects associated with H(1) or H(3) antagonism.

MeSH terms

  • Administration, Intranasal
  • Administration, Oral
  • Drug Discovery / methods*
  • Histamine H1 Antagonists / administration & dosage
  • Histamine H1 Antagonists / chemistry
  • Histamine H1 Antagonists / pharmacology
  • Histamine H1 Antagonists / therapeutic use
  • Histamine H3 Antagonists / administration & dosage
  • Histamine H3 Antagonists / chemistry
  • Histamine H3 Antagonists / pharmacology
  • Histamine H3 Antagonists / therapeutic use
  • Humans
  • Models, Molecular
  • Phthalazines / administration & dosage*
  • Phthalazines / chemistry
  • Phthalazines / pharmacology*
  • Phthalazines / therapeutic use
  • Protein Conformation
  • Receptors, Histamine H1 / chemistry
  • Receptors, Histamine H1 / metabolism*
  • Receptors, Histamine H3 / metabolism*
  • Rhinitis / drug therapy*


  • Histamine H1 Antagonists
  • Histamine H3 Antagonists
  • Phthalazines
  • Receptors, Histamine H1
  • Receptors, Histamine H3
  • phthalazine