The URB937 drug is a small molecule, peripheral inhibitor of the enzyme fatty acid amide hydrolase (FAAH; IC50=26.8 nM). The FAAH enzyme breaks down the naturally occurring endocannabinoid anandamide, and inhibition of FAAH by URB937 results in elevated anandamide levels and increased cannabinoid receptor signaling. The drug has antitussive effects in in vitro and in vivo models of cough, and exhibits profound analgesic effects in a variety of animal models of nociceptive, inflammatory and neurogenic pain, indicating it will have broad clinical application and commercial potential. Importantly, the drug does not penetrate the blood-brain barrier and therefore exerts its action only in peripheral tissues. This feature differentiates URB937 from most other FAAH inhibitors currently in development, and significantly enhances the safety profile of the drug compared to global FAAH inhibitors. Formal (GLP) IND-enabling safety/pharmacology studies were completed with URB937 and these predict the drug will have no safety issues or side-effects.
The URB937 drug is excluded from the brain by a transporter with a pharmacology resembling BCRP, but is free to act on peripheral FAAH. In chronic cough, the site of action is predicted to be the vagal sensory nerve. Here inhibition of FAAH-catalyzed metabolism of anandamide allows for persistent activation of the CB1 receptors, which limits Vagus nerve activation and the cough reflex.