The discovery of quinoline based single-ligand human H 1 and H 3 receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 24; pp. 5855 - 5859
• Main Authors: Procopiou, Panayiotis A, Ancliff, Rachael A, Gore, Paul M, Hancock, Ashley P, Hodgson, Simon T, Holmes, Duncan S, Keeling, Steven P, Looker, Brian E, Parr, Nigel A, Rowedder, James E, Slack, Robert J
• Format: Journal Article
• Language: English
• Published: England 15-12-2016
• Subjects: Dose-Response Relationship, Drug; Drug Discovery; Histamine H1 Antagonists - chemical synthesis; Histamine H1 Antagonists - chemistry; Histamine H1 Antagonists - pharmacology; Histamine H3 Antagonists - chemical synthesis; Histamine H3 Antagonists - chemistry; Histamine H3 Antagonists - pharmacology; Humans; Ligands; Molecular Structure; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Receptors, Histamine H1 - metabolism; Receptors, Histamine H3 - metabolism; Structure-Activity Relationship; Quinoline; Nasal congestion; Single ligand; Allergic rhinitis; HH histamine receptor antagonist
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.11.022

A novel series of potent quinoline-based human H
and H
bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis associated nasal congestion, were identified. Compound 18b had slightly lower H
potency (pA
8.8 vs 9.7 for the clinical goldstandard azelastine), and H
potency (pK
9.1vs 6.8 for azelastine), better selectivity over α
, α
and hERG, similar duration of action, making 18b a good back-up compound to our previous candidate, but with a more desirable profile.