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

Authors: Martin J. GunthorpeSara Luis HannanDarren SmartJeffrey C. JermanSandra ArpinoGraham D. SmithStephen BroughJim WrightJulie EgertonSarah C. LappinVicky A. HollandKim WinbornMervyn ThompsonHarshad K. RamiAndrew Randall and John B. Davis


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-
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 (pKi  7.6) with activity at
rat (pKi  7.5) and guinea pig (pKi  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.