2. Academic Validation
  3. Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain

Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain

  • ACS Med Chem Lett. 2015 Jan 30;6(4):419-24. doi: 10.1021/ml500479v.
Mark D Andrews 1,  Kerry Af Forselles 1,  Kevin Beaumont 2,  Sébastien R G Galan 1,  Paul A Glossop 1,  Mathilde Grenie 1,  Alan Jessiman 1,  Amy S Kenyon 1,  Graham Lunn 1,  Graham Maw 1,  Robert M Owen 3,  David C Pryde 3,  Dannielle Roberts 1,  Thien Duc Tran 1
Affiliations

Affiliations

  • 1 Worldwide Medicinal Chemistry and Biology, Pfizer Global Research and Development, Sandwich Laboratories , Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom.
  • 2 Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
  • 3 Worldwide Medicinal Chemistry, Pfizer Neusentis , Granta Park, Cambridge CB21 6GS, United Kingdom.
PMID: 25893043 DOI: 10.1021/ml500479v
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.

Keywords

PF-05105679; TRP channel; TRPM8; clinical tool; hypothermia; ion channel; pain; thermoregulation.

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