title: Characterization of 2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (JNJ-39729209) as a novel TRPV1 antagonist.
abstract: As an integrator of multiple nociceptive and/or inflammatory stimuli, TRPV1 is an attractive therapeutic target for the treatment of various painful disorders. Several TRPV1 antagonists have been advanced into clinical trials and the initial observations suggest that TRPV1 antagonism may be associated with mild hyperthermia and thermal insensitivity in man. However, no clinical efficacy studies have been described to date, making an assessment of risk:benefit impossible. Furthermore, it is not clear whether these early observations are representative of all TRPV1 antagonists and whether additional clinical studies with novel TRPV1 antagonists are required in order to understand optimal compound characteristics. In the present study we describe 2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (JNJ-39729309) as a novel, TRPV1 antagonist. JNJ-39729209 displaced tritiated resiniferotoxin binding to TRPV1 and prevented TRPV1 activation by capsaicin, protons and heat. In-vivo, JNJ-39729209 blocked capsaicin-induced hypotension, induced a mild hyperthermia and inhibited capsaicin-induced hypothermia in a dose dependent manner. JNJ-39729209 showed significant efficacy against carrageenan- and CFA-evoked thermal hyperalgesia and exhibited significant anti-tussive activity in a guinea-pig model of capsaicin-induced cough. In pharmacokinetic studies, JNJ-39729209 was found to have low clearance, a moderate volume of distribution, good oral bioavailability and was brain penetrant. On the basis of these findings, JNJ-39729209 represents a structurally novel TRPV1 antagonist with potential for clinical development. The advancement of JNJ-39729209 into human clinical trials could be useful in further understanding the analgesic potential of TRPV1 antagonists.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Maher
authors.forename: Anindya
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Hong
authors.initials: H
authors.lastname: Ao
authors.forename: Nadia
authors.initials: N
authors.lastname: Swanson
authors.forename: Nyan-Tsz
authors.initials: NT
authors.lastname: Wu
authors.forename: Jamie
authors.initials: J
authors.lastname: Freedman
authors.forename: Mena
authors.initials: M
authors.lastname: Kansagara
authors.forename: Brian
authors.initials: B
authors.lastname: Scott
authors.forename: Dong H
authors.initials: DH
authors.lastname: Li
authors.forename: William A
authors.initials: WA
authors.lastname: Eckert
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Kia
authors.initials: K
authors.lastname: Sepassi
authors.forename: Michele
authors.initials: M
authors.lastname: Rizzolio
authors.forename: Anne
authors.initials: A
authors.lastname: Fitzgerald
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Branstetter
authors.forename: Jason C
authors.initials: JC
authors.lastname: Rech
authors.forename: Alec D
authors.initials: AD
authors.lastname: Lebsack
authors.forename: J Guy
authors.initials: JG
authors.lastname: Breitenbucher
authors.forename: Alan D
authors.initials: AD
authors.lastname: Wickenden
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Chaplan
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002460:Cell Line; D002986:Clinical Trials as Topic; D003371:Cough / Q000188:drug therapy; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007022:Hypotension / Q000188:drug therapy; D008297:Male; D051379:Mice; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C568132:(2-(2,6-dichlorobenzyl)thiazolo(5,4-d)pyrimidin-7-yl)-(4-trifluoromethylphenyl)amine; D011743:Pyrimidines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D013844:Thiazoles