title: Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain.
abstract: The transient receptor potential (TRP) family of ion channels comprises nonselective cation channels that respond to a wide range of chemical and thermal stimuli. TRPM8, a member of the melastatin subfamily, is activated by cold temperatures (<28 °C), and antagonists of this channel have the potential to treat cold induced allodynia and hyperalgesia. However, TRPM8 has also been implicated in mammalian thermoregulation and antagonists have the potential to induce hypothermia in patients. We report herein the identification and optimization of a series of TRPM8 antagonists that ultimately led to the discovery of PF-05105679. The clinical finding with this compound will be discussed, including both efficacy and its ability to affect thermoregulation processes in humans.
authors.affiliation: Worldwide Medicinal Chemistry and Biology, Pfizer Global Research and Development, Sandwich Laboratories , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Andrews
authors.affiliation: Worldwide Medicinal Chemistry and Biology, Pfizer Global Research and Development, Sandwich Laboratories , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: Kerry
authors.initials: K
authors.lastname: Af Forselles
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Beaumont
authors.affiliation: Worldwide Medicinal Chemistry and Biology, Pfizer Global Research and Development, Sandwich Laboratories , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: Sébastien R G
authors.initials: SR
authors.lastname: Galan
authors.affiliation: Worldwide Medicinal Chemistry and Biology, Pfizer Global Research and Development, Sandwich Laboratories , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Glossop
authors.affiliation: Worldwide Medicinal Chemistry and Biology, Pfizer Global Research and Development, Sandwich Laboratories , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Grenie
authors.affiliation: Worldwide Medicinal Chemistry and Biology, Pfizer Global Research and Development, Sandwich Laboratories , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Jessiman
authors.affiliation: Worldwide Medicinal Chemistry and Biology, Pfizer Global Research and Development, Sandwich Laboratories , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Kenyon
authors.affiliation: Worldwide Medicinal Chemistry and Biology, Pfizer Global Research and Development, Sandwich Laboratories , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Lunn
authors.affiliation: Worldwide Medicinal Chemistry and Biology, Pfizer Global Research and Development, Sandwich Laboratories , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Maw
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Neusentis , Granta Park, Cambridge CB21 6GS, United Kingdom.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Owen
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Neusentis , Granta Park, Cambridge CB21 6GS, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Pryde
authors.affiliation: Worldwide Medicinal Chemistry and Biology, Pfizer Global Research and Development, Sandwich Laboratories , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: Dannielle
authors.initials: D
authors.lastname: Roberts
authors.affiliation: Worldwide Medicinal Chemistry and Biology, Pfizer Global Research and Development, Sandwich Laboratories , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: Thien Duc
authors.initials: TD
authors.lastname: Tran
keywords: PF-05105679; TRP channel; TRPM8; clinical tool; hypothermia; ion channel; pain; thermoregulation