title: Identification and biological characterization of 6-aryl-7-isopropylquinazolinones as novel TRPV1 antagonists that are effective in models of chronic pain.
abstract: Vanilloid receptor 1 (VR1, TRPV1) is a cation-selective ion channel that is expressed on primary afferent neurons and is upregulated following inflammation and nerve damage. Blockers of this channel may have utility in the treatment of chronic nociceptive and neuropathic pain. Here, we describe the optimization from a high throughput screening hit, of a series of 6-aryl-7-isopropylquinazolinones that are TRPV1 antagonists in vitro. We also demonstrate that one compound is active in vivo against capsaicin-induced hyperalgesia and in models of neuropathic and nociceptive pain in the rat.
authors.affiliation: Novartis Institutes for Biomedical Research, London WC1E 6BS, UK. andrew.culshaw@novartis.com
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Culshaw
authors.forename: Stuart
authors.initials: S
authors.lastname: Bevan
authors.forename: Martin
authors.initials: M
authors.lastname: Christiansen
authors.forename: Prafula
authors.initials: P
authors.lastname: Copp
authors.forename: Andrew
authors.initials: A
authors.lastname: Davis
authors.forename: Clare
authors.initials: C
authors.lastname: Davis
authors.forename: Alex
authors.initials: A
authors.lastname: Dyson
authors.forename: Edward K
authors.initials: EK
authors.lastname: Dziadulewicz
authors.forename: Lee
authors.initials: L
authors.lastname: Edwards
authors.forename: Hendrikus
authors.initials: H
authors.lastname: Eggelte
authors.forename: Alyson
authors.initials: A
authors.lastname: Fox
authors.forename: Clive
authors.initials: C
authors.lastname: Gentry
authors.forename: Alex
authors.initials: A
authors.lastname: Groarke
authors.forename: Allan
authors.initials: A
authors.lastname: Hallett
authors.forename: Terance W
authors.initials: TW
authors.lastname: Hart
authors.forename: Glyn A
authors.initials: GA
authors.lastname: Hughes
authors.forename: Sally
authors.initials: S
authors.lastname: Knights
authors.forename: Peter
authors.initials: P
authors.lastname: Kotsonis
authors.forename: Wai
authors.initials: W
authors.lastname: Lee
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lyothier
authors.forename: Andrew
authors.initials: A
authors.lastname: McBryde
authors.forename: Peter
authors.initials: P
authors.lastname: McIntyre
authors.forename: George
authors.initials: G
authors.lastname: Paloumbis
authors.forename: Moh
authors.initials: M
authors.lastname: Panesar
authors.forename: Sadhana
authors.initials: S
authors.lastname: Patel
authors.forename: Max-Peter
authors.initials: MP
authors.lastname: Seiler
authors.forename: Mohammed
authors.initials: M
authors.lastname: Yaqoob
authors.forename: Kaspar
authors.initials: K
authors.lastname: Zimmermann
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D016466:CHO Cells; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D002908:Chronic Disease; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D015162:Micronucleus Tests; D008862:Microsomes, Liver / Q000378:metabolism; D010146:Pain / Q000188:drug therapy*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D011799:Quinazolines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human