RESUMEN
Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aß levels in rats and nonhuman primates and CSF Aß levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Precursor de Proteína beta-Amiloide/antagonistas & inhibidores , Óxidos S-Cíclicos/farmacología , Descubrimiento de Drogas , Tiadiazinas/farmacología , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Óxidos S-Cíclicos/síntesis química , Óxidos S-Cíclicos/química , Perros , Relación Dosis-Respuesta a Droga , Humanos , Macaca fascicularis , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiadiazinas/síntesis química , Tiadiazinas/químicaRESUMEN
TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Amidas/farmacología , Inhibidores Enzimáticos/farmacología , Pirrolidinas/química , Tartratos/química , Proteína ADAM17 , Amidas/síntesis química , Amidas/química , Animales , Disponibilidad Biológica , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Estructura Molecular , RatasRESUMEN
The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Inhibidores de Proteasas/química , Tartratos/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animales , Sitios de Unión , Simulación por Computador , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Ratas , Relación Estructura-Actividad , Tartratos/síntesis química , Tartratos/farmacocinéticaRESUMEN
A novel series of TNF-alpha convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.
