title: Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade.
abstract: Capsaicin, the active ingredient in some pain-relieving creams, is an agonist of a nonselective cation channel known as the transient receptor potential vanilloid type 1 (TRPV1). The pain-relieving mechanism of capsaicin includes desensitization of the channel, suggesting that TRPV1 antagonism may be a viable pain therapy approach. In agreement with the above notion, several TRPV1 antagonists have been reported to act as antihyperalgesics. Here, we report the in vitro and in vivo characterization of a novel and selective TRPV1 antagonist, N-(4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamide I (AMG 517), and compare its pharmacology with that of a closely related analog, tert-butyl-2-(6-([2-(acetylamino)-1,3-benzothiazol-4-yl]oxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenylcarbamate (AMG8163). Both AMG 517 and AMG8163 potently and completely antagonized capsaicin, proton, and heat activation of TRPV1 in vitro and blocked capsaicin-induced flinch in rats in vivo. To support initial clinical investigations, AMG 517 was evaluated in a comprehensive panel of toxicology studies that included in vivo assessments in rodents, dogs, and monkeys. The toxicology studies indicated that AMG 517 was generally well tolerated; however, transient increases in body temperature (hyperthermia) were observed in all species after AMG 517 dosing. To further investigate this effect, we tested and showed that the antipyretic, acetaminophen, suppressed the hyperthermia caused by TRPV1 blockade. We also showed that repeated administration of TRPV1 antagonists attenuated the hyperthermia response, whereas the efficacy in capsaicin-induced flinch model was maintained. In conclusion, these studies suggest that the transient hyperthermia elicited by TRPV1 blockade may be manageable in the development of TRPV1 antagonists as therapeutic agents. However, the impact of TRPV1 antagonist-induced hyperthermia on their clinical utility is still unknown.
authors.affiliation: Department of Neuroscience, MS-29-2-B, One Amgen Center Dr., Thousand Oaks, CA 91320-1799, USA. ngavva@amgen.com
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Bannon
authors.forename: David N
authors.initials: DN
authors.lastname: Hovland
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Lehto
authors.forename: Lana
authors.initials: L
authors.lastname: Klionsky
authors.forename: Sekhar
authors.initials: S
authors.lastname: Surapaneni
authors.forename: David C
authors.initials: DC
authors.lastname: Immke
authors.forename: Charles
authors.initials: C
authors.lastname: Henley
authors.forename: Leyla
authors.initials: L
authors.lastname: Arik
authors.forename: Annette
authors.initials: A
authors.lastname: Bak
authors.forename: James
authors.initials: J
authors.lastname: Davis
authors.forename: Nadia
authors.initials: N
authors.lastname: Ernst
authors.forename: Gal
authors.initials: G
authors.lastname: Hever
authors.forename: Rongzhen
authors.initials: R
authors.lastname: Kuang
authors.forename: Licheng
authors.initials: L
authors.lastname: Shi
authors.forename: Rami
authors.initials: R
authors.lastname: Tamir
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.forename: Weiya
authors.initials: W
authors.lastname: Wang
authors.forename: Gary
authors.initials: G
authors.lastname: Zajic
authors.forename: Dawn
authors.initials: D
authors.lastname: Zhu
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Louis
authors.forename: Ella
authors.initials: E
authors.lastname: Magal
authors.forename: James J S
authors.initials: JJ
authors.lastname: Treanor
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001831:Body Temperature / Q000187:drug effects; D016466:CHO Cells; D002211:Capsaicin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D015195:Drug Design; D005260:Female; D005334:Fever / Q000188:drug therapy* / Q000378:metabolism; D005620:Freund's Adjuvant / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D013686:Telemetry
chemical_list: D018712:Analgesics, Non-Narcotic; D052160:Benzothiazoles; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D011743:Pyrimidines; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C519014:tert-butyl-2-(6-((2-(acetylamino)-1,3-benzothiazol-4-yl)oxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenylcarbamate; D005620:Freund's Adjuvant; D002211:Capsaicin