Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase.
ChemMedChem
; 13(20): 2177-2188, 2018 10 22.
Article
em En
| MEDLINE
| ID: mdl-30113139
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 Phaseâ
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Óxidos N-Cíclicos
/
Inibidores Enzimáticos
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Amidoidrolases
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Analgésicos
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
ChemMedChem
Assunto da revista:
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Portugal