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℃; 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].

Clinical trial: A randomised challenge trial showed that the 3% topical SB705498 cream was clinically well tolerated and had target specific pharmacodynamic activity. However there were no clinically significant differences on pruritus induced by either challenge agent in comparison to placebo. Thus, SB705498 is unlikely to be of symptomatic benefit for histaminergic or non-histaminergic induced itch [3].

Reference:
[1] Gunthorpe MJ, Hannan SL, Smart D, Jerman JC, Arpino S, Smith GD, Brough S, Wright J, Egerton J, Lappin SC, Holland VA, Winborn K, Thompson M, Rami HK, Randall A, Davis JB.  Characterization of SB-705498, a potent and selective vanilloid receptor-1 (VR1/TRPV1) antagonist that inhibits the capsaicin-, acid-, and heat-mediated activation of the receptor. J Pharmacol Exp Ther. 2007 Jun;321(3):1183-92.
[2] Rami HK, Thompson M, Stemp G, Fell S, Jerman JC, Stevens AJ, Smart D, Sargent B, Sanderson D, Randall AD, Gunthorpe MJ, Davis JB.  Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development. Bioorg Med Chem Lett. 2006 Jun 15;16(12):3287-91.
[3] Gibson RA, Robertson J, Mistry H, McCallum S, Fernando D, Wyres M, Yosipovitch G.  A randomised trial evaluating the effects of the TRPV1 antagonist SB705498 on pruritus induced by histamine, and cowhage challenge in healthy volunteers. PLoS One. 2014 Jul 21;9(7):e100610.