Identification and biological evaluation of 4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide, a high affinity TRPV1 (VR1) vanilloid receptor antagonist.
High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the structure-activity relationships by parallel synthesis identified the essential pharmacophoric elements for antagonism that permitted further optimization via targeted synthesis to provide a potent orally bioavailable and selective TRPV1 modulator 41 active in several in vivo models.
Swanson
Devin M
DM
Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.
Dubin
Adrienne E
AE
Shah
Chandra
C
Nasser
Nadia
N
Chang
Leon
L
Dax
Scott L
SL
Jetter
Michele
M
Breitenbucher
J Guy
JG
Liu
Changlu
C
Mazur
Curt
C
Lord
Brian
B
Gonzales
Lisa
L
Hoey
Kenway
K
Rizzolio
Michele
M
Bogenstaetter
Michael
M
Codd
Ellen E
EE
Lee
Doo H
DH
Zhang
Sui-Po
SP
Chaplan
Sandra R
SR
Carruthers
Nicholas I
NI
D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001831:Body Temperature / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin; D002460:Cell Line; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced / Q000517:prevention & control; D007473:Ion Channels / Q000819:agonists / Q000037:antagonists & inhibitors*; D008297:Male; D010147:Pain Measurement; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels
C500065:4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide; D000631:Aminopyridines; D000700:Analgesics; D007473:Ion Channels; D010879:Piperazines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; D002211:Capsaicin; D002118:Calcium