title: Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans.
abstract: The transient receptor potential (subfamily M, member 8; TRPM8) is a nonselective cation channel localized in primary sensory neurons, and is a candidate for cold thermosensing, mediation of cold pain, and bladder overactivity. Studies with TRPM8 knockout mice and selective TRPM8 channel blockers demonstrate a lack of cold sensitivity and reduced cold pain in various rodent models. Furthermore, TRPM8 blockers significantly lower body temperature. We have identified a moderately potent (IC50 = 103 nM), selective TRPM8 antagonist, PF-05105679 [(R)-3-[(1-(4-fluorophenyl)ethyl)(quinolin-3-ylcarbonyl)amino]methylbenzoic acid]. It demonstrated activity in vivo in the guinea pig bladder ice water and menthol challenge tests with an IC50 of 200 nM and reduced core body temperature in the rat (at concentrations >1219 nM). PF-05105679 was suitable for acute administration to humans and was evaluated for effects on core body temperature and experimentally induced cold pain, using the cold pressor test. Unbound plasma concentrations greater than the IC50 were achieved with 600- and 900-mg doses. The compound displayed a significant inhibition of pain in the cold pressor test, with efficacy equivalent to oxycodone (20 mg) at 1.5 hours postdose. No effect on core body temperature was observed. An unexpected adverse event (hot feeling) was reported, predominantly periorally, in 23 and 36% of volunteers (600- and 900-mg dose, respectively), which in two volunteers was nontolerable. In conclusion, this study supports a role for TRPM8 in acute cold pain signaling at doses that do not cause hypothermia.
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.) Wendy.winchester@pfizer.com.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Winchester
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Katrina
authors.initials: K
authors.lastname: Gore
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Sophie
authors.initials: S
authors.lastname: Glatt
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Wendy
authors.initials: W
authors.lastname: Petit
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Gardiner
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Kelly
authors.initials: K
authors.lastname: Conlon
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Michael
authors.initials: M
authors.lastname: Postlethwaite
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Pierre-Philippe
authors.initials: PP
authors.lastname: Saintot
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Sonia
authors.initials: S
authors.lastname: Roberts
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: James R
authors.initials: JR
authors.lastname: Gosset
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Tomomi
authors.initials: T
authors.lastname: Matsuura
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Mark D
authors.initials: MD
authors.lastname: Andrews
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Paul A
authors.initials: PA
authors.lastname: Glossop
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Palmer
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Nicola
authors.initials: N
authors.lastname: Clear
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Susie
authors.initials: S
authors.lastname: Collins
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: Kevin
authors.initials: K
authors.lastname: Beaumont
authors.affiliation: Pfizer Limited, Neusentis Research Unit, Granta Park, Cambridge, United Kingdom (W.J.W., K.G., S.G., D.S.R.); Genito-Urinary Research Unit (W.J.W., J.C.G., K.C., M.P., P.-P.S., D.S.R.), Research Statistics (K.G., S.C.), Drug Safety, Research and Development (S.R.), Pharmacokinetics, Dynamics and Metabolism (J.R.G., T.M., K.B.), and Worldwide Medicinal Chemistry (M.D.A., P.A.G., M.J.P.), Pfizer Global Research and Development, Sandwich, Kent, United Kingdom; Pfizer Clinical Research Unit, Lenniksebaan, Brussels, Belgium (W.P.); and PharmaTherapeutics Pharmaceutical Sciences, Pfizer Limited, Sandwich, United Kingdom (N.C.).
authors.forename: David S
authors.initials: DS
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D003080:Cold Temperature; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D010098:Oxycodone / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D049990:Membrane Transport Modulators; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D010098:Oxycodone