RESUMEN
Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (-)-12a, (-)-12i, (-)-12l-m. The required (-)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15. Based on comparative profile of FAAH potency, metabolic stability in liver microsome, liability of inhibiting major hCYP450 isoforms, rat PK, and brain penetration ability, two SAR optimized compounds, (-)-12l and (-)-12m, were selected for efficacy study in rat model of chemotherapy-induced peripheral neuropathy (CIPN). Both the compounds exhibited dose related antihyperalgesic effects, when treated with 3-30â¯mg/kg po for 7â¯days. The effects at 30â¯mg/kg are comparable to that of PF-04457845 (10â¯mg/kg) and Tramadol (40â¯mg/kg).
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Neuralgia/tratamiento farmacológico , Amidohidrolasas/metabolismo , Animales , Antineoplásicos/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Estructura Molecular , Neuralgia/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
A concise and efficient one-pot synthesis of novel N-fused tricyclic derivatives has been developed by using the Groebke-Blackburn-Bienaymé (GBB) reaction, which involved the reaction of 3-amino-1H-indazoles, aldehydes and isonitriles to afford 2-aryl-5H-imidazo[1,2-b]indazol-3-amine derivatives via a formal [4 + 1] cycloaddition reaction. Furthermore, we describe an unprecedented reaction of chromone-3-carboxaldehydes with 3-amino-1H-indazoles to afford (2-hydroxyphenyl)(pyrimido[1,2-b]indazol-3-yl)methanones in one-pot at ambient temperature. This protocol features a robust method for the one-step construction of new tricyclic rings, column chromatography free methods with a clean reaction profile, high yields, operational simplicity and it tolerates a diverse collection of reactants.