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

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 degrees C), and antagonists of this channel have t...

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Published in:ACS medicinal chemistry letters Vol. 6; no. 4; pp. 419 - 424
Main Authors: Andrews, Mark D., af Forselles, Kerry, Beaumont, Kevin, Galan, Sebastien R. G., Glossop, Paul A., Grenie, Mathilde, Jessiman, Alan, Kenyon, Amy S., Lunn, Graham, Maw, Graham, Owen, Robert M., Pryde, David C., Roberts, Dannielle, Thien Duc Tran
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 09.04.2015
Subjects:
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
pain
DESIGN
SERIES
PP-05105679
clinical tool
BODY-TEMPERATURE
thermoregulation
TRP channel
PHARMACOLOGICAL BLOCKADE
DRUG-DISCOVERY
POTENT
hypothermia
ion channel
CHANNELS
TRPM8
PF-05105679
ISSN:1948-5875, 1948-5875
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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 degrees 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.
AbstractList 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.
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 degrees 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.
Author Beaumont, Kevin
Glossop, Paul A.
Thien Duc Tran
Jessiman, Alan
Roberts, Dannielle
Lunn, Graham
Owen, Robert M.
Pryde, David C.
Kenyon, Amy S.
Maw, Graham
Andrews, Mark D.
af Forselles, Kerry
Galan, Sebastien R. G.
Grenie, Mathilde
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  givenname: Sebastien R. G.
  orcidid: 0000-0002-6241-0238
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  givenname: Robert M.
  surname: Owen
  fullname: Owen, Robert M.
  email: robert.owen@pfizer.com
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  givenname: David C.
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  surname: Thien Duc Tran
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Issue 4
Keywords pain
DESIGN
SERIES
PP-05105679
clinical tool
BODY-TEMPERATURE
thermoregulation
TRP channel
PHARMACOLOGICAL BLOCKADE
DRUG-DISCOVERY
POTENT
hypothermia
ion channel
CHANNELS
TRPM8
PF-05105679
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Snippet The transient receptor potential (TRP) family of ion channels comprises nonselective cation channels that respond to a wide range of chemical and thermal...
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Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
Title Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain
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