Structure-activity studies of a novel series of 5,6-fused heteroaromatic ureas as TRPV1 antagonists.
Novel 5,6-fused heteroaromatic ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that 4-aminoindoles and indazoles are the preferential cores for the attachment of ureas. Bulky electron-withdrawing groups in the para-position of the aromatic ring of the urea substituents imparted the best in vitro potency at TRPV1. The most potent derivatives were assessed in in vivo inflammatory and neuropathic pain models. Compound 46, containing the indazole core and a 3,4-dichlorophenyl group appended to it via a urea linker, demonstrated in vivo analgesic activity upon oral administration. This derivative also showed selectivity versus other receptors in the CEREP screen and exhibited acceptable cardiovascular safety at levels exceeding the therapeutic dose.
Drizin
Irene
I
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Il 60064, USA. irene.drizin@abbott.com
Gomtsyan
Arthur
A
Bayburt
Erol K
EK
Schmidt
Robert G
RG
Zheng
Guo Zhu
GZ
Perner
Richard J
RJ
DiDomenico
Stanley
S
Koenig
John R
JR
Turner
Sean C
SC
Jinkerson
Tammie K
TK
Brown
Brian S
BS
Keddy
Ryan G
RG
McDonald
Heath A
HA
Honore
Prisca
P
Wismer
Carol T
CT
Marsh
Kennan C
KC
Wetter
Jill M
JM
Polakowski
James S
JS
Segreti
Jason A
JA
Jarvis
Michael F
MF
Faltynek
Connie R
CR
Lee
Chih-Hung
CH
D000818:Animals; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014508:Urea