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
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.
Assuntos
Antiparkinsonianos/síntese química , Inibidores de Catecol O-Metiltransferase , Oxidiazóis/síntese química , Animais , Antiparkinsonianos/química , Antiparkinsonianos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Interações Medicamentosas , Técnicas In Vitro , Levodopa/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
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.