Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders.
BACKGROUND: Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that hydrolyzes the endocannabinoid anandamide and related amidated signaling lipids. Genetic or pharmacological inactivation of FAAH produces analgesic, anti-inflammatory, anxiolytic, and antidepressant phenotypes without showing the undesirable side effects of direct cannabinoid receptor agonists, indicating that FAAH may be a promising therapeutic target. OBJECTIVES: This review highlights advances in the development of FAAH inhibitors of different mechanistic classes and their in vivo efficacy. Also highlighted are advances in technology for the in vitro and in vivo selectivity assessment of FAAH inhibitors employing activity-based protein profiling (ABPP) and click chemistry-ABPP, respectively. Recent reports on structure-based drug design for human FAAH generated by protein engineering using interspecies active site conversion are also discussed. METHODS: The literature searches of Medline and SciFinder databases were used. CONCLUSIONS: There has been tremendous progress in our understanding in FAAH and development of FAAH inhibitors with in vivo efficacy, selectivity, and drug like pharmacokinetic properties.
Ahn
Kay
K
Pfizer Global Research and Development, Groton/New London Laboratories, Groton, CT 06340.
Johnson
Douglas S
DS
Cravatt
Benjamin F
BF