The discovery of phthalazinone-based human H1 and H3 single-ligand antagonists suitable for intranasal administration for the treatment of allergic rhinitis.
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Procopiou PA, Browning C, Buckley JM, Clark KL, Fechner L, Gore PM, Hancock AP, Hodgson ST, Holmes DS, Kranz M, Looker BE, Morriss KM, Parton DL, Russell LJ, Slack RJ, Sollis SL, Vile S, Watts CJ
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.
- PubMed ID
- 21381763 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Azelastine Cytochrome P450 2D6 IC 50 (nM) 1000 N/A N/A Details Azelastine Histamine H1 receptor Kd (nM) 0.2 N/A N/A Details Azelastine Histamine H1 receptor Ki (nM) 1.26 N/A N/A Details Chlorpheniramine Histamine H1 receptor Ki (nM) 7 N/A N/A Details