RESUMEN
We report the design and synthesis of novel 5,6-diarylated pyridin-2(1H)-one derivatives as pharmacophoric PDE10A inhibitors. This highly potent molecular scaffold was developed from an inactive diarylpyridine-2-amine derivative 3b by extensive and systematic analogue synthesis and SAR analysis. Further optimization of the scaffold resulted in identification of pyridin-2(1H)-one 18b as a lead compound with good potency (IC50 = 1.6 nM) and selectivity (>6000-fold) over other related PDEs but with a poor pharmacokinetic profile. Careful metabolite profiling of 18b revealed that poor systemic exposure in rats (Cmax = 44 ng/mL; AUC0-t = 359 ng · h/mL) at 10 mg/kg was due to the formation of O-glucuronide conjugate by phase 2 metabolism. The structure of the glucuronide metabolite was confirmed by retention time and LC-MS/MS fragmentation matching with the synthetic glucuronide 26. The problem of low exposure of 18b was effectively addressed by its conversion to an acetate prodrug 25b, which upon oral dosing resulted in an improved pharmacokinetic profile (Cmax = 359 ng.h/mL; AUC0-t = 2436 ng.h/mL) and a desirable brain to plasma ratio of 1.2. The prodrug 25b showed good efficacy in selected rodent models of psychosis.
Asunto(s)
Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/efectos de los fármacos , Piridonas/síntesis química , Piridonas/farmacología , Acetatos/síntesis química , Acetatos/farmacocinética , Animales , Antipsicóticos/síntesis química , Antipsicóticos/farmacología , Área Bajo la Curva , Perros , Diseño de Fármacos , Femenino , Glucurónidos/metabolismo , Macaca fascicularis , Masculino , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Inhibidores de Fosfodiesterasa/farmacocinética , Profármacos , Psicosis Inducidas por Sustancias/tratamiento farmacológico , Piridonas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The transient receptor potential canonical (TRPC) channels have gained interest as potential therapeutic targets for respiratory diseases, neurological disorders, cardiovascular disorders, pain, cancer and several other pathological conditions. The TRPC receptor family consists of seven isoforms (C1-C7) and has been divided into three subfamilies based on structural and functional similarities. Several pharmaceutical companies and academic institutes are currently exploring the potential of these nonselective cation channels as therapeutic targets using small molecule inhibitors or modulators. This review covers patents on TRPC receptor modulators published from 2002 to 2014. The review mainly focuses on TRPC receptor target biology, small and large molecule modulators and their therapeutic potential.