title: The discovery of quinoline based single-ligand human H1and H3receptor antagonists.
abstract: A novel series of potent quinoline-based human H1and H3bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis associated nasal congestion, were identified. Compound 18b had slightly lower H1potency (pA28.8 vs 9.7 for the clinical goldstandard azelastine), and H3potency (pKi9.1vs 6.8 for azelastine), better selectivity over α1A, α1Band hERG, similar duration of action, making 18b a good back-up compound to our previous candidate, but with a more desirable profile.
authors.affiliation: Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. Electronic address: pan.a.procopiou@gsk.com.
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Procopiou
authors.affiliation: Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Ancliff
authors.affiliation: Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Gore
authors.affiliation: Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Ashley P
authors.initials: AP
authors.lastname: Hancock
authors.affiliation: Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Hodgson
authors.affiliation: Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Duncan S
authors.initials: DS
authors.lastname: Holmes
authors.affiliation: Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Keeling
authors.affiliation: Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Looker
authors.affiliation: Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Parr
authors.affiliation: R&D Platform Technology and Science, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: James E
authors.initials: JE
authors.lastname: Rowedder
authors.affiliation: Respiratory Biology, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Slack
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D006634:Histamine H1 Antagonists; D054828:Histamine H3 Antagonists; D008024:Ligands; D011804:Quinolines; D011969:Receptors, Histamine H1; D018100:Receptors, Histamine H3; C037219:quinoline
keywords: Allergic rhinitis; H(1)H(3) histamine receptor antagonist; Nasal congestion; Quinoline; Single ligand