title: Design and synthesis of peripherally restricted transient receptor potential vanilloid 1 (TRPV1) antagonists.
abstract: Transient receptor potential vanilloid 1 (TRPV1) channel antagonists may have clinical utility for the treatment of chronic nociceptive and neuropathic pain. We recently advanced a TRPV1 antagonist, 3 (AMG 517), into clinical trials as a new therapy for the treatment of pain. However, in addition to the desired analgesic effects, this TRPV1 antagonist significantly increased body core temperature following oral administration in rodents. Here, we report one of our approaches to eliminate or minimize the on-target hyperthermic effect observed with this and other TRPV1 antagonists. Through modifications of our clinical candidate, 3 a series of potent and peripherally restricted TRPV1 antagonists have been prepared. These analogues demonstrated on-target coverage in vivo but caused increases in body core temperature, suggesting that peripheral restriction was not sufficient to separate antagonism mediated antihyperalgesia from hyperthermia. Furthermore, these studies demonstrate that the site of action for TRPV1 blockade elicited hyperthermia is outside the blood-brain barrier.
authors.affiliation: Chemistry Research and Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. ntamayo@amgen.com.
authors.forename: Nuria
authors.initials: N
authors.lastname: Tamayo
authors.forename: Hongyu
authors.initials: H
authors.lastname: Liao
authors.forename: Markian M
authors.initials: MM
authors.lastname: Stec
authors.forename: Xianghong
authors.initials: X
authors.lastname: Wang
authors.forename: Partha
authors.initials: P
authors.lastname: Chakrabarti
authors.forename: Dan
authors.initials: D
authors.lastname: Retz
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Doherty
authors.forename: Sekhar
authors.initials: S
authors.lastname: Surapaneni
authors.forename: Rami
authors.initials: R
authors.lastname: Tamir
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Bannon
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001812:Blood-Brain Barrier / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D002211:Capsaicin; D005334:Fever / Q000139:chemically induced; D008297:Male; D010147:Pain Measurement; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D013686:Telemetry
chemical_list: D000700:Analgesics; D052160:Benzothiazoles; D011810:Quinoxalines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D002211:Capsaicin