title: 7-tert-Butyl-6-(4-chloro-phenyl)-2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4-one, a classic polymodal inhibitor of transient receptor potential vanilloid type 1 with a reduced liability for hyperthermia, is analgesic and ameliorates visceral hypersensitivity.
abstract: The therapeutic potential of transient receptor potential vanilloid type 1 (TRPV1) antagonists for chronic pain has been recognized for more than a decade. However, preclinical and clinical data revealed that acute pharmacological blockade of TRPV1 perturbs thermoregulation, resulting in hyperthermia, which is a major hurdle for the clinical development of these drugs. Here, we describe the properties of 7-tert-butyl-6-(4-chloro-phenyl)-2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4-one (BCTP), a TRPV1 antagonist with excellent analgesic properties that does not induce significant hyperthermia in rodents at doses providing maximal analgesia. BCTP is a classic polymodal inhibitor of TRPV1, blocking activation of the human channel by capsaicin and low pH with IC(50) values of 65.4 and 26.4 nM, respectively. Similar activity was observed with rat TRPV1, and the inhibition by BCTP was competitive and reversible. BCTP also blocked heat-induced activation of TRPV1. In rats, the inhibition of capsaicin-induced mechanical hyperalgesia was observed with a D(50) value of 2 mg/kg p.o. BCTP also reversed visceral hypersensitivity and somatic inflammatory pain, and using a model of neuropathic pain in TRPV1 null mice we confirmed that its analgesic properties were solely through the inhibition of TRPV1. We were surprised to find that BCTP administered orally induced only a maximal 0.6°C increase in core body temperature at the highest tested doses (30 and 100 mg/kg), contrasting markedly with N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide (AMG517), a clinically tested TRPV1 antagonist, which induced marked hyperthermia (>1°C) at doses eliciting submaximal reversal of capsaicin-induced hyperalgesia. The combined data indicate that TRPV1 antagonists with a classic polymodal inhibition profile can be identified where the analgesic action is separated from the effects on body temperature.
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, United Kingdom.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Nash
authors.forename: Peter
authors.initials: P
authors.lastname: McIntyre
authors.forename: Alex
authors.initials: A
authors.lastname: Groarke
authors.forename: Elliot
authors.initials: E
authors.lastname: Lilley
authors.forename: Andrew
authors.initials: A
authors.lastname: Culshaw
authors.forename: Allan
authors.initials: A
authors.lastname: Hallett
authors.forename: Moh
authors.initials: M
authors.lastname: Panesar
authors.forename: Alyson
authors.initials: A
authors.lastname: Fox
authors.forename: Stuart
authors.initials: S
authors.lastname: Bevan
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D052160:Benzothiazoles / Q000009:adverse effects; D001831:Body Temperature / Q000187:drug effects; D001833:Body Temperature Regulation / Q000187:drug effects; D016466:CHO Cells; D002211:Capsaicin / Q000494:pharmacology; D006224:Cricetinae; D005334:Fever / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced; D006967:Hypersensitivity / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000009:adverse effects; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013871:Thiones / Q000494:pharmacology*; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C576950:7-tert-butyl-6-(4-chlorophenyl)-2-thioxo-2,3-dihydro-1H-pyrido(2,3-d)pyrimidin-4-one; D000700:Analgesics; D052160:Benzothiazoles; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D011743:Pyrimidines; D011744:Pyrimidinones; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D013871:Thiones; D050051:Transient Receptor Potential Channels; D002211:Capsaicin