Emergence - Emergence

Preclinical evaluation of first-in-class modulators of TREK channels, a new target for the treatment of pain. – TREK-ANALGESIA

Modulators of TREK-1 channels, a novel target against pain

60% of patients feel their pain is inadequately controlled. This project aims to develop a new class of more effective, more personalized painkillers with less or no side effects.

Improving the management of pain

Chronic pain affects, in Europe, one in five adults. Despite a large therapeutic arsenal, over 60% of patients feel that their pain is not adequately controlled. <br />Treatment with morphine, a ladder 3 analgesic, is often accompanied by side effects (constipation, nausea, vomiting, respiratory depression, dependence). The Neuro-dol team recently demonstrated that activation of the potassium channels called TREK-1 was essential for the analgesic effect of morphine but was not involved in the adverse effects of the opioid. The objective of this project is to develop and optimize molecules able to activate the TREK-1 channels and having an analgesic activity. This project aims to develop a new class of more effective, more personalized painkillers with less or even no side effects.

The ICCF-CESMA team identified molecules capable of activating the TREK-1 channels and pharmacological studies have shown that these molecules possess remarkable antinociceptive (analgesic) activity. We studied the relationship between structures and activities in order to deduce the pharmacophore (pharmacologically active parts of the molecules). These results allowed us to optimize the properties of the molecules so that they become drug candidates. The medicinal properties are determined: the ability to activate the channels of the K2P family including TREK-1, the pharmacological profile (80 targets), the analgesic activity in multiple pain models (pain profiling) the ADMET properties (solubility, stability, permeability, clearance, protein binding, genotoxicity, cardiotoxicity).

We developed activators of the potassium channels TREK-1, which have excellent analgesic efficacy in particular for post-operative, inflammatory and neuropathic pain. These molecules have no adverse effects including constipation, cardiotoxicity and genotoxicity. Finally the molecules possess good solubility and stability properties. The license of intellectual property is being transferred to the SAS INNOPAIN to continue the regulatory preclinical and clinical development of these drug candidates.

We have developed molecules which activate the potassium channel TREK-1, located downstream of the mu opioid receptor (MOR). These activators have therapeutic effects very promising analgesic and lack the side effects associated with morphine.

doi: 10.1016/j.ejmech.2014.01.049 - Synthesis and SAR study of substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel.
doi:10.1038/ncomms3941 - Activation of TREK-1 by morphine results in analgesia without adverse side effects.
WO 2011033241 - Pain relief compounds

Pain affects nearly 70 million people on the 7 principal world markets, causing a great degree of discomfort among patients and an enormous economic and social burden. Inadequate pain control and side-effects associated with current analgesics has encouraged the development of original analgesics with novel modes of action to address the unmet needs of patients.
Amongst the mechanisms of action involved in pain transmission and perception, TWIK-Related K+ channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs. It has been reported that TREK-1 -/- mice were more sensitive than wild-type mice to painful stimuli, suggesting that activation of TREK-1 could result in pain inhibition.
We have identified and patented a novel class of analgesics which target TREK-1 and personal data allow us to suspect that these compounds would do not present the side effects usually associated with morphine for the treatment of chronic pain. The preliminary data obtained are very promising and prompted us to further develop these molecules as drug candidates.
We now wish to pursue our strategy of "lead optimization" by completing the screening of these molecules (synthesis, pharmacology, ADME, toxicity) in order to select those that will belong to our future business pipeline. The project should validate the proof of concept necessary for the exploitation of the patent by reducing the associated risks and adding commercial value to the molecules. We envisage a technology transfer via the creation of a company which would bring the molecules to the early clinical stages before licensing the rights for the late clinical development and commercialization of the analgesic drugs.

Project coordinator

Madame Sylvie DUCKI (Institut de Chimie de Clermont-Ferrand - Conception et Synthèse de molécules antalgiques (CESMA)) – sylvie.ducki@sigma-clermont.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


AuValo Auvergne Valorisation - SATT Grand Centre
IPMC Institut de Pharmacologie Moléculaire et Cellulaire-Eq Physiologie moléculaire et physiopathologie des canaux ioniques
NEURO-DOL Institut Neuro-Dol - Eq Pharmacologie Fondamentale et Clinique de la Douleur
ICCF Institut de Chimie de Clermont-Ferrand - Conception et Synthèse de molécules antalgiques (CESMA)

Help of the ANR 257,204 euros
Beginning and duration of the scientific project: December 2012 - 24 Months

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