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 (Ͼ1°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.

TRPA1 mediates the hypothermic action of acetaminophen

“…In our studies the hypothermic effects of APAP were abolished by a similar systemic treatment with RTX. However, the effect of APAP could not be ascribed to TRPV1 agonism as hypothermia was retained in Trpv1 −/− mice and unaffected by systemic administration of a dose of a TRPV1 antagonist that exerts a maximal analgesic effect 18 , in agreement with previous studies 7 . TRPA1 is predominantly expressed in TRPV1 containing sensory neurons 43 .…”

“…Since TRPV1 inhibition evokes hyperthermia 16 17 and TRPV1 activation elicits hypothermia, we re-evaluated the effects of APAP in wild-type mice treated with the TRPV1 antagonist BCTP 18 , and in Trpv1 −/− mice. The basal body temperature was not different in Trpv1 +/+ and Trpv1 −/− mice (Trpv1 +/+ 37.8 ± 0.1 °C; Trpv1 −/− 37.8 ± 0.1 °C, p > 0.2, n = 11 groups of 6 for each genotype).…”

Efficient Synthesis of Uracil‐Derived Hexa‐ and Tetrahydropyrido[2,3‐d]pyrimidines

“…This interest is a result of their various pharmacological activities. For example, uracil‐derived pyrido[2,3‐ d ]pyrimidines have a range of biological properties, such as phosphodiesterase 2 (PDE 2) inhibition,1a or antihypertensive,1b,1c cardiotonic,2 analgesic,3a antiviral,3b anti‐inflammatory,4 antimicrobial,5,6 or anticancer activities7,8 (Figure 1). Therefore, the synthesis of diverse structures belonging to this class of compounds is important.…”

Contemporary views on inflammatory pain mechanisms: TRPing over innate and microglial pathways

“…Given TRPV1 and TRPA1’s seminal roles in the signaling of inflammatory pain, there has been considerable interest in the development of high-affinity antagonists against them 40 , 41 . Indeed, there are endogenous inhibitors of TRPV1 and TRPA1, including resolvins and maresins, which are among the group of lipid mediators that are involved in resolving inflammation 42 – 44 .…”