Fatty acid amide hydrolase (FAAH) can be targeted for the treatment of pain associated with various medical conditions. Herein we report the design and synthesis of a novel series of… Click to show full abstract
Fatty acid amide hydrolase (FAAH) can be targeted for the treatment of pain associated with various medical conditions. Herein we report the design and synthesis of a novel series of heterocyclic‐N‐carboxamide FAAH inhibitors that have a good alignment of potency, metabolic stability and selectivity for FAAH over monoacylglycerol lipase (MAGL) and carboxylesterases (CEs). Lead optimization efforts carried out with benzotriazolyl‐ and imidazolyl‐N‐carboxamide series led to the discovery of clinical candidate 8 l (3‐(1‐(cyclohexyl(methyl)carbamoyl)‐1H‐imidazol‐4‐yl)pyridine 1‐oxide; BIA 10‐2474) as a potent and long‐acting inhibitor of FAAH. However, during a Phase I clinical trial with compound 8 l, unexpected and unpredictable serious neurological adverse events occurred, affecting five healthy volunteers, including the death of one subject.
               
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