RT Journal Article
SR Electronic
T1 7-<em>tert</em>-Butyl-6-(4-Chloro-Phenyl)-2-Thioxo-2,3-Dihydro-1<em>H</em>-Pyrido[2,3-<em>d</em>]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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 389
OP 398
DO 10.1124/jpet.112.191932
VO 342
IS 2
A1 Nash, Mark S.
A1 McIntyre, Peter
A1 Groarke, Alex
A1 Lilley, Elliot
A1 Culshaw, Andrew
A1 Hallett, Allan
A1 Panesar, Moh
A1 Fox, Alyson
A1 Bevan, Stuart
YR 2012
UL http://jpet.aspetjournals.org/content/342/2/389.abstract
AB 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 IC50 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 D50 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 (&gt;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.