title: 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.
abstract: 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 Ca(2+)-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 (IC(50) = 3 nM)-, acid (pH 5.3)-, or heat (50 degrees C; IC(50) = 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.
authors: Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK. martin_j_gunthorpe@gsk.com
authors: Martin J
authors: MJ
authors: Gunthorpe
authors: Sara Luis
authors: SL
authors: Hannan
authors: Darren
authors: D
authors: Smart
authors: Jeffrey C
authors: JC
authors: Jerman
authors: Sandra
authors: S
authors: Arpino
authors: Graham D
authors: GD
authors: Smith
authors: Stephen
authors: S
authors: Brough
authors: Jim
authors: J
authors: Wright
authors: Julie
authors: J
authors: Egerton
authors: Sarah C
authors: SC
authors: Lappin
authors: Vicky A
authors: VA
authors: Holland
authors: Kim
authors: K
authors: Winborn
authors: Mervyn
authors: M
authors: Thompson
authors: Harshad K
authors: HK
authors: Rami
authors: Andrew
authors: A
authors: Randall
authors: John B
authors: JB
authors: Davis
mesh_terms: D000143:Acids / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006168:Guinea Pigs; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000143:Acids; D011759:Pyrrolidines; C512301:SB 705498; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014508:Urea; D002211:Capsaicin