Identification and biological characterization of 6-aryl-7-isopropylquinazolinones as novel TRPV1 antagonists that are effective in models of chronic pain.
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.
Culshaw
Andrew J
AJ
Novartis Institutes for Biomedical Research, London WC1E 6BS, UK. andrew.culshaw@novartis.com
Bevan
Stuart
S
Christiansen
Martin
M
Copp
Prafula
P
Davis
Andrew
A
Davis
Clare
C
Dyson
Alex
A
Dziadulewicz
Edward K
EK
Edwards
Lee
L
Eggelte
Hendrikus
H
Fox
Alyson
A
Gentry
Clive
C
Groarke
Alex
A
Hallett
Allan
A
Hart
Terance W
TW
Hughes
Glyn A
GA
Knights
Sally
S
Kotsonis
Peter
P
Lee
Wai
W
Lyothier
Isabelle
I
McBryde
Andrew
A
McIntyre
Peter
P
Paloumbis
George
G
Panesar
Moh
M
Patel
Sadhana
S
Seiler
Max-Peter
MP
Yaqoob
Mohammed
M
Zimmermann
Kaspar
K
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
D011799:Quinazolines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human