In vitro structure-activity relationship and in vivo characterization of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 antagonists.
The synthesis and structure-activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.
Perner
Richard J
RJ
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. richard.j.perner@abbott.com
DiDomenico
Stanley
S
Koenig
John R
JR
Gomtsyan
Arthur
A
Bayburt
Erol K
EK
Schmidt
Robert G
RG
Drizin
Irene
I
Zheng
Guo Zhu
GZ
Turner
Sean C
SC
Jinkerson
Tammie
T
Brown
Brian S
BS
Keddy
Ryan G
RG
Lukin
Kurill
K
McDonald
Heath A
HA
Honore
Prisca
P
Mikusa
Joe
J
Marsh
Kennan C
KC
Wetter
Jill M
JM
George
Karen St
KS
Jarvis
Michael F
MF
Faltynek
Connie R
CR
Lee
Chih-Hung
CH
D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
D000700:Analgesics; D007191:Indazoles; D007546:Isoquinolines; C523417:N-(3-trichloromethyl-4-(8-azabicyclo(3.2.1)octan-8-yl)benzyl)-N'-(indazol-4-yl)urea; D010671:Phenylurea Compounds; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; D014508:Urea