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Fatty acid amide hydrolase (FAAH) inhibitor design and preclinical studies: lessons learned from BIA 10-2474 and the
Alessia Catalano1, Filomena Fezza2, Andrea Duranti3
1Department of Pharmacy - Pharmaceutical Sciences, University of Bari Aldo Moro, Bari, Italy.
Introduction:
BIA 10-2474 is a fatty acid amide hydrolase (FAAH) inhibitor that was developed as a treatment for anxiety and pain, due to its ability to increase the endocannabinoid tone. It was released for clinical trials and subsequently withdrawn due to its neurological adverse reactions Several hypotheses were suggested to justify the toxicity of the drug, but the exact responsible mechanism has not been fully established.
Areas Covered:
This review paper summarises the concerns arising from the development of BIA 10-2474. The authors highlight the lessons learnt from the development of BIA 10-2474 and discuss how advanced methodologies can assist scientists to face the challenges ahead. This article is primarily based on literature derived from the Reaxys® (queries: 'FAAH inhibitors,' 'fatty acid amidase inhibitors,' and 'fatty acid amide hydrolase inhibitors') focusing on the past decade. Cross references were retrieved from the early papers obtained.
Expert Opinion:
Rodent and human FAAH have different 3D structures and interact differently with exogenous molecules. Thus, any candidate drug should be tested also on human FAAH and/or on human specimens. Safety measures to prevent untoward outcomes in first-in-human phase I clinical trials have been suggested, and further studies are urgently needed to address these dangerous circumstances.
