Ario Pharma is currently progressing a TRPA1 lead optimisation project, focusing on chronic pain
Pain is one of the most common reasons for seeking medical care; with an estimated 40 million physician visits and 4 billion lost working days per year. Existing treatments for neuropathic pain and inflammatory pain are currently inadequate due to poor efficacy and drug safety profiles and have resulted in the search for drugs that work by alternate mechanisms.
TRPA1 has been shown to play a critical role in chronic pain and is widely considered an attractive target for the development of novel analgaesics.
TRPA1 is a member of the TRP (Transient Receptor Potential) superfamily comprising six transmembrane domains but with a distinct ankyrin repeat region at the N-terminal domain, assembling as a tetrameric non-selective cation channel. TRPA1 channels are activated by mechanical stretch, cold and a wide range of compounds (mainly, but not exclusively, through covalent binding to N-terminal cysteine residues). Specific subsets of sensory neurons express TRPA1 which is upregulated following inflammation or nerve injury. Activators of TRPA1 include pungent or noxious compounds (such as allyl isothiocyanate and cinnamaldehyde) that can elicit pain, and a variety of endogenous electrophilic molecules generated following tissue injury and inflammation. The key role of TRPA1 in pain signalling has been supported by studies using TRPA1 knockout mouse, use of selective TRPA1 antagonists in a variety of preclinical pain models and human genetics (which have demonstrated an association between gain-of-function mutations in human TRPA1 and familial episodic pain syndrome).Ario Pharma is actively working to identify potent, safe, orally bioavailable small molecule TRPA1 antagonists to treat chronic pain.