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NEUROPHARMACOLOGY

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

Neurology and Gastrointestinal Centre of Excellence for Drug Discovery (M.J.G., S.L.H., D.S., J.C.J., G.D.S., S.B., J.W., J.E., S.C.L., V.A.H., K.W., M.T., H.K.R., A.R., J.B.D.) and Discovery Research (S.A.), GlaxoSmithKline, Harlow, Essex, United Kingdom

Vanilloid receptor-1 (TRPV1) is a nonselective cation channel, predominantly expressed by sensory neurons, which plays a key role in the detection of noxious painful stimuli such as capsaicin, acid, and heat. TRPV1 antagonists may represent novel therapeutic agents for the treatment of a range of conditions including chronic pain, migraine, and gastrointestinal disorders. Here we describe the in vitro pharmacology of N-(2-bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea (SB-705498), a novel TRPV1 antagonist identified by lead optimization of N-(2-bromophenyl)-N'-{2-[ethyl(3-methylphenyl)amino]ethyl}urea (SB-452533), which has now entered clinical trials. 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 (pK_i = 7.6) with activity at rat (pK_i = 7.5) and guinea pig (pK_i = 7.3) orthologs. Whole-cell patch-clamp electrophysiology was used to confirm and extend these findings, demonstrating that SB-705498 can potently inhibit the multiple modes of receptor activation that may be relevant to the pathophysiological role of TRPV1 in vivo: 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). Interestingly, SB-705498 also showed a degree of voltage dependence, suggesting an effective enhancement of antagonist action at negative potentials such as those that might be encountered in neurons in vivo. The selectivity of SB-705498 was defined by broad receptor profiling and other cellular assays in which it showed little or no activity versus a wide range of ion channels, receptors, and enzymes. SB-705498 therefore represents a potent and selective multimodal TRPV1 antagonist, a pharmacological profile that has contributed to its definition as a suitable drug candidate for clinical development.

Address correspondence to: Dr. Martin J. Gunthorpe, Neurology and GI-CEDD, GlaxoSmithKline, Harlow, Essex CM19 5AW, UK. E-mail: martin_j_gunthorpe{at}gsk.com

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