Design and synthesis of 6-phenylnicotinamide derivatives as antagonists of TRPV1.
6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.
Westaway
Susan M
SM
Neurology CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. sue.m.westaway@gsk.com
Thompson
Mervyn
M
Rami
Harshad K
HK
Stemp
Geoffrey
G
Trouw
Leontine S
LS
Mitchell
Darren J
DJ
Seal
Jon T
JT
Medhurst
Stephen J
SJ
Lappin
Sarah C
SC
Biggs
James
J
Wright
James
J
Arpino
Sandra
S
Jerman
Jeffrey C
JC
Cryan
Jennifer E
JE
Holland
Vicky
V
Winborn
Kim Y
KY
Coleman
Tanya
T
Stevens
Alexander J
AJ
Davis
John B
JB
Gunthorpe
Martin J
MJ
D000284:Administration, Oral; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002211:Capsaicin / Q000737:chemistry; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D007249:Inflammation; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry*
C540067:6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide; D052160:Benzothiazoles; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D009536:Niacinamide; D002211:Capsaicin