RESUMEN
The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Alphabeta42 in an APP-YAC transgenic mouse model.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Fragmentos de Péptidos/antagonistas & inhibidores , Purinas/química , Purinas/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide/genética , Péptidos beta-Amiloides/metabolismo , Animales , Humanos , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/metabolismo , Purinas/farmacología , Receptores Notch/metabolismo , Relación Estructura-ActividadRESUMEN
A potent family of spirocyclic nicotinyl aminobenzamide selective HDAC1/HDAC2 inhibitors (SHI-1:2) is profiled. The incorporation of a biaryl zinc-binding motif into a nicotinyl scaffold resulted in enhanced potency and selectivity versus HDAC3, but also imparted hERG activity. It was discovered that increasing polar surface area about the spirocycle attenuates this liability. Compound 12 induced a 4-fold increase in acetylated histone H2B in an HCT-116 xenograft model study with acute exposure, and inhibited tumor growth in a 21-day efficacy study with qd dosing.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Canales de Potasio Éter-A-Go-Go/metabolismo , Inhibidores de Histona Desacetilasas , Niacinamida/síntesis química , Niacinamida/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Animales , Antineoplásicos/química , Benzamidas/síntesis química , Benzamidas/química , Benzamidas/farmacología , Técnicas Químicas Combinatorias , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Células HCT116 , Histona Desacetilasas , Histonas/análisis , Humanos , Ratones , Ratones Desnudos , Estructura Molecular , Niacinamida/química , Isoformas de Proteínas , Compuestos de Espiro/química , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.
Asunto(s)
Derivados del Benceno/síntesis química , Derivados del Benceno/farmacología , Inhibidores de Histona Desacetilasas , Modelos Moleculares , Derivados del Benceno/química , Sitios de Unión/efectos de los fármacos , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Estructura Molecular , Isoformas de Proteínas , Proteínas Represoras , Relación Estructura-ActividadRESUMEN
This communication highlights the development of a nicotinamide series of histone deacetylase inhibitors within the benzamide structural class. Extensive exploration around the nicotinamide core led to the discovery of a class I selective HDAC inhibitor that possesses excellent intrinsic and cell-based potency, acceptable ancillary pharmacology, favorable pharmacokinetics, sustained pharmacodynamics in vitro, and achieves in vivo efficacy in an HCT116 xenograft model.
