RESUMEN
SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.
Asunto(s)
Amidas/química , Anilidas/química , Proteínas Hedgehog/metabolismo , Piridinas/química , Amidas/síntesis química , Amidas/farmacología , Anilidas/síntesis química , Anilidas/farmacología , Animales , Bencimidazoles/química , Carcinoma Basocelular/tratamiento farmacológico , Línea Celular , Neoplasias Cerebelosas/tratamiento farmacológico , Proteínas Hedgehog/antagonistas & inhibidores , Humanos , Meduloblastoma/tratamiento farmacológico , Ratones , Ratones Desnudos , Piridinas/síntesis química , Piridinas/farmacología , Transducción de Señal , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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 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).