Receptor

Histamine

Histamine H1 receptor

Surgery

Bioavailability

Chemistry

In vitro

Nose

Antagonist

Nasal congestion

Azelastine

Potency

Biochemistry

Medicine

Nasal administration

Pharmacology

Journal of Medicinal Chemistry

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.

The Discovery of Phthalazinone-Based Human H<sub>1</sub>and H<sub>3</sub>Single-Ligand Antagonists Suitable for Intranasal Administration for the Treatment of Allergic Rhinitis

The Discovery of Phthalazinone-Based Human H1and H3Single-Ligand Antagonists Suitable for Intranasal Administration for the Treatment of Allergic Rhinitis

The Discovery of Phthalazinone-Based Human H₁and H₃Single-Ligand Antagonists Suitable for Intranasal Administration for the Treatment of Allergic Rhinitis