N-Tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl biaryl carboxamides as antagonists of TRPV1.
Starting from the high throughput screening hit (3), novel N-tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl carboxamides have been identified as potent antagonists of the ion channel TRPV1. The N-quinolinylnicotinamide (46) showed excellent potency at human, guinea pig and rat TRPV1, a favourable in vitro DMPK profile and activity in an in vivo model of inflammatory pain.
Westaway
Susan M
SM
Neurology and GI Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. sue.m.westaway@gsk.com
Chung
Ying-Kit
YK
Davis
John B
JB
Holland
Vicky
V
Jerman
Jeffrey C
JC
Medhurst
Stephen J
SJ
Rami
Harshad K
HK
Stemp
Geoffrey
G
Stevens
Alexander J
AJ
Thompson
Mervyn
M
Winborn
Kim Y
KY
Wright
James
J
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001549:Benzamides; D007546:Isoquinolines; D011804:Quinolines; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D002211:Capsaicin