title: 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.
abstract: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.
authors.forename: Devin M
authors.initials: DM
authors.lastname: Swanson
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Dubin
authors.forename: Chandra
authors.initials: C
authors.lastname: Shah
authors.forename: Nadia
authors.initials: N
authors.lastname: Nasser
authors.forename: Leon
authors.initials: L
authors.lastname: Chang
authors.forename: Scott L
authors.initials: SL
authors.lastname: Dax
authors.forename: Michele
authors.initials: M
authors.lastname: Jetter
authors.forename: J Guy
authors.initials: JG
authors.lastname: Breitenbucher
authors.forename: Changlu
authors.initials: C
authors.lastname: Liu
authors.forename: Curt
authors.initials: C
authors.lastname: Mazur
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.forename: Lisa
authors.initials: L
authors.lastname: Gonzales
authors.forename: Kenway
authors.initials: K
authors.lastname: Hoey
authors.forename: Michele
authors.initials: M
authors.lastname: Rizzolio
authors.forename: Michael
authors.initials: M
authors.lastname: Bogenstaetter
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Codd
authors.forename: Doo H
authors.initials: DH
authors.lastname: Lee
authors.forename: Sui-Po
authors.initials: SP
authors.lastname: Zhang
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Chaplan
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
mesh_terms: 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
chemical_list: 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