RESUMO
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.
Assuntos
Amidoidrolases/antagonistas & inibidores , Analgésicos/farmacologia , Óxidos N-Cíclicos/farmacologia , Inibidores Enzimáticos/farmacologia , Piridinas/farmacologia , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Analgésicos/química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ensaios Clínicos Fase I como Assunto , Óxidos N-Cíclicos/administração & dosagem , Óxidos N-Cíclicos/efeitos adversos , Óxidos N-Cíclicos/química , Desenho de Fármacos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/química , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
A regio- and stereocontrolled total synthesis of (-)-allosamizoline is described. The key steps for this synthesis are ring-closing metathesis to form the cyclopentene core, halocyclization to afford the oxazoline ring, and finally stereoselective alkene radical addition followed by an alkene isomerization reaction to install the hydroxymethyl group. (-)-Allosamizoline was prepared in a total of 13 steps and 22% overall yield.
