PF-04457845 (FAAH Inhibitor)
PF-04457845 is an oral, selective small molecule inhibitor of the fatty acid amide hydrolase (FAAH), the principal catabolic enzyme for a class of bioactive lipids including N-arachidonyl ethanolamine (anandamide; AEA), a key endocannabinoid.
PF-04457845 was evaluated in several Pfizer-sponsored and investigator-sponsored Phase 1 and Phase 2 clinical studies. SpringWorks is exploring the potential of PF-04457845 in CNS disorders, both as a monotherapy and in combination with other investigational agents.
How It Is Designed to Work
FAAH is an integral membrane enzyme that hydrolyzes the fatty amide family of lipid transmitters, including AEA, an important neurotransmitter in the brain that regulates a wide range of biological processes including pain, inflammation and cognitive/emotional state. AEA has been shown to activate central cannabinoid receptor 1 (CB1R) and peripheral cannabinoid receptor 2 (CB2R). FAAH contributes to the attenuation of AEA signaling by rapidly hydrolyzing AEA to arachidonic acid (AA) and ethanolamine (ETA). Clinical studies have demonstrated that inhibition of FAAH can increase brain AEA levels and lead to activation of central cannabinoid receptor 1 (CB1); this mechanism has the potential to treat a variety of neurological disorders.
- D’Souza, DC., et al. “Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial” Lancet Psychiatry 2018; DOI:10.1016/S2215-0366(18)30427-9.
- George, T., “FAAH inhibition for treatment of problematic cannabis use” Lancet Psychiatry 2018; DOI:10.1016/S2215-0366(18)30462-0.