• Generated from in-house research programme
• Potentially profound analgesic response
• Effective in pre-clinical pain models

The FAAH enzyme metabolises the endocannabinoids (ECs) which are neurotransmitters acting on a range of different receptors. Inhibit FAAH, and elevated EC levels appear in the nervous system. Amongst the receptors which the ECs act upon are the CB1, CB2 and TRPV1 receptors, stimulation of which has been shown to relieve pain. ECs also act on the PPARα receptor which is known to reduce inflammation.

FAAH inhibitors

May cause powerful analgesic response

Since endocannabinoids are only produced on demand, it may be that FAAH inhibitors, such as V158866, can selectively increase the local levels of neurotransmitter in tissues. This could deliver a powerful analgesic and anti-inflammatory response, without the side effects that more widespread cannabinoid receptor activation can generate.

Vernalis identified Fatty Acid Amide Hydrolase as a target that might be particularly amenable to our research techniques back in 2007. V158866 was the lead molecule to emerge from this research programme, demonstrating our ability to generate promising candidates that go on to full pipeline development.

Leading players in the pharmaceutical industry are paying particular interest to FAAH inhibitor molecules, with a number of them currently in development by the major companies. Additional possible indications for the class include the treatment of anxiety and depression.

V158866 has been shown to be a potent and selective slowly reversible inhibitor of human FAAH1 (IC₅₀ 24nM) It has been evaluated in a series of pre-clinical pain models and has been shown to have efficacy in:

• Carageenan-induced thermal hyperalgesia
• Carageenan-induced inflammation
• Mono-iodoacetate model of osteoarthritis
• Chronic constriction injury model of neuropathic pain

It has no significant effect on locomotor function in pre-clinical models, even at high doses.

A range of pre-clinical safety and pharmacokinetic studies were conducted on V158866.

Clinical studies started in March 2011. A double-blind, placebo controlled study investigating single and multiple ascending doses is being conducted in healthy male volunteers. The objective of the study is to identify doses of V158866 that are both safe and well tolerated and to measure the compound’s effect on FAAH activity and endocannabinoid levels.

Pre-clinical sudies completed, clinical studies were initiated in March 2011 with results expected during the year.