RESUMEN
Discovery of a highly selective, potent, and safe non-carboxylic acid, non-hydantoin inhibitor of aldose reductase (AR) capable of potently blocking the excess glucose flux through the polyol pathway that prevails under diabetic conditions has been a long-standing challenge. In response, we did high-throughput screening of our internal libraries of compounds and identified 6-phenylsulfonylpyridazin-2H-3-one, 8, which showed modest inhibition of AR, both in vitro and in vivo. Initial structure-activity relationships concentrated on phenyl substituents and led to 6-(2,4-dichlorophenylsulfonyl)-2H-pyridazin-3-one, 8l, which was more potent than 8, both in vitro and in vivo. Incorporation of extant literature findings with other aldose reductase inhibitors, including zopolrestat, resulted in the title inhibitor, 19m, which is one of the most potent and highly selective non-carboxylic acid, non-hydantoin inhibitors of AR yet described (IC50, 1 nM; ED90 vs sciatic nerve sorbitol and fructose, respectively, 0.8 and 4.0 mg/kg). In rats, its oral bioavailability is 98% and it has a favorable plasma t(1/2) (26 +/- 3 h).
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Aldehído Reductasa/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/síntesis química , Piridazinas/síntesis química , Sulfonas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Fructosa/metabolismo , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Cristalino/metabolismo , Masculino , Piridazinas/química , Piridazinas/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/antagonistas & inhibidores , Nervio Ciático/efectos de los fármacos , Nervio Ciático/metabolismo , Sorbitol/metabolismo , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
We report here a novel sorbitol dehydrogenase inhibitor, 16, that shows very high oral potency (50 microg/kg) in normalizing elevated fructose levels in the sciatic nerve of chronically diabetic rats and sustained duration of action (>24 h). Furthermore, 16 shows attractive pharmaceutical properties, including good solubility in simulated human gastric fluid, excellent Caco-2 Papp, moderate lipophilicity, and metabolic stability for achieving good oral absorption and long duration of action.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , L-Iditol 2-Deshidrogenasa/antagonistas & inhibidores , Pirimidinas/síntesis química , Triazinas/síntesis química , Administración Oral , Animales , Células CACO-2 , Diabetes Mellitus/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Fructosa/metabolismo , Humanos , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Nervio Ciático/efectos de los fármacos , Nervio Ciático/metabolismo , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacologíaRESUMEN
We report here on the discovery path that led to a structurally unprecedented non-hydantoin, non-carboxylic acid aldose reductase inhibitor, 24, which shows remarkably potent oral activity in normalizing elevated sorbitol levels and, more significantly, fructose levels in the sciatic nerve of chronically diabetic rats, with ED(90) values of 0.8 and 3 mpk, respectively. It is well absorbed in rats (oral bioavailability, 98%) and has a long plasma t(1/2) (26 +/- 3 h).