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Discovery of a Potent, Long‐Acting, and CNS‐Active Inhibitor (BIA 10‐2474) of Fatty Acid Amide Hydrolase
Author(s) -
Kiss László E.,
Beliaev Alexandre,
Ferreira Humberto S.,
Rosa Carla P.,
Bonifácio Maria João,
Loureiro Ana I.,
Pires Nuno M.,
Palma P. Nuno,
SoaresdaSilva Patrício
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800393
Subject(s) - fatty acid amide hydrolase , monoacylglycerol lipase , carboxamide , chemistry , pharmacology , amide , potency , drug discovery , stereochemistry , biochemistry , medicine , endocannabinoid system , receptor , antagonist , in vitro , cannabinoid receptor
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)‐1 H ‐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.