RESUMEN
Novel routes to 2-trifluoromethyl-nicotinic acid derivatives have been developed involving synthesis of the pyridine ring. These pyridyl compounds serve as key intermediates in the manufacture of the recently discovered COMT inhibitor, 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)pyridine 1-oxide.
Asunto(s)
Ácidos Nicotínicos/síntesis química , Ácidos Nicotínicos/química , Nitrilos/químicaRESUMEN
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.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Analgésicos/farmacología , Óxidos N-Cíclicos/farmacología , Inhibidores Enzimáticos/farmacología , Piridinas/farmacología , Administración Oral , Analgésicos/administración & dosificación , Analgésicos/efectos adversos , Analgésicos/química , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ensayos Clínicos Fase I como Asunto , Óxidos N-Cíclicos/administración & dosificación , Óxidos N-Cíclicos/efectos adversos , Óxidos N-Cíclicos/química , Diseño de Fármacos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/química , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Estructura Molecular , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Novel nitrocatechol-substituted heterocycles were designed and evaluated for their ability to inhibit catechol-O-methyltransferase (COMT). Replacement of the pyrazole core of the initial hit 4 with a 1,2,4-oxadiazole ring resulted in a series of compounds endowed with longer duration of COMT inhibition. Incorporation of a pyridine N-oxide residue at position 3 of the 1,2,4-oxadiazole ring led to analogue 37f, which was found to possess activity comparable to entacapone and lower toxicity in comparison to tolcapone. Lead structure 37f was systematically modified in order to improve selectivity and duration of COMT inhibition as well as to minimize toxicity. Oxadiazole 37d (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide (BIA 9-1067)) was identified as a long-acting, purely peripheral inhibitor, which is currently under clinical evaluation as an adjunct to L-Dopa therapy of Parkinson's disease.