Document Detail

The Discovery of Phthalazinone-Based Human H(1) and H(3) Single-Ligand Antagonists Suitable for Intranasal Administration for the Treatment of Allergic Rhinitis.
MedLine Citation:
PMID:  21381763     Owner:  NLM     Status:  Publisher    
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.
Panayiotis A Procopiou; Christopher Browning; Jennifer M Buckley; Kenneth L Clark; Lise Fechner; Paul M Gore; Ashley P Hancock; Simon T Hodgson; Duncan S Holmes; Michael Kranz; Brian E Looker; Karen M L Morriss; Daniel L Parton; Linda J Russell; Robert J Slack; Steven L Sollis; Sadie Vile; Clarissa J Watts
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-3-7
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  -     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-3-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Departments of Medicinal Chemistry, ‡Respiratory Biology, §Drug Metabolism and Pharmacokinetics, and ∥Cheminformatics, GlaxoSmithKline Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
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