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PKi: 7.6 for human TRPV1 receptor

Vanilloid receptor-1 (TRPV1) is a nonselective cation channel, predominantly expressed by sensory neurons, playing a key role in the detection of noxious painful stimuli such as capsaicin, heat, and acid. TRPV1 antagonists may represent novel therapeutic agents for the treatment of a range of conditions including chronic pain, gastrointestinal disorders, and migraine. SB-705498 is a potent, selective and orally bioavailable TRPV1 antagonist.

In vitro: Using a Ca2+-based fluorometric imaging plate reader (FLIPR) assay, SB-705498 was shown to be a potent competitive antagonist of the capsaicin-mediated activation of the human TRPV1 receptor (pKi = 7.6) with activity at rat (pKi = 7.5) and guinea pig (pKi = 7.3) orthologs. SB-705498 caused rapid and reversible inhibition of the capsaicin (IC50 = 3 nM)-, acid (pH 5.3)-, or heat (50°C; IC50 = 6 nM)-mediated activation of human TRPV1 (at =70 mV) [1].

In vivo: Having initially demonstrated that SB-705498 showed good overall in vitro efficacy and oral bioavailability in rat, the in vivo activity of SB-705498 was investigated in the capsaicin-induced secondary hyperalgesia model9 in the rat. This model demonstrates the compound’s antagonist activity in vivo against the specific TRPV1 agonist capsaicin. As an early indicator of potential pharmacodynamic activity, SB-705498 showed excellent activity at 10 and 30 mg/kg po with good reversal of allodynia. Furthermore, SB-705498 was also shown to give 80% reversal of allodynia in the guinea pig FCA model at 10 mg/kg po [2].

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