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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Bibliographic Details
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
Online Access:Get more information
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Summary: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.
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ISSN:1948-5875
1948-5875
DOI:10.1021/ml500479v