RESUMO
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.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Fragmentos de Peptídeos/antagonistas & inibidores , Purinas/química , Purinas/uso terapêutico , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Humanos , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismo , Purinas/farmacologia , Receptores Notch/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Inibidores de Histona Desacetilases , Niacinamida/síntese química , Niacinamida/farmacologia , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Animais , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Benzamidas/farmacologia , Técnicas de Química Combinatória , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Células HCT116 , Histona Desacetilases , Histonas/análise , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Niacinamida/química , Isoformas de Proteínas , Compostos de Espiro/química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Derivados de Benzeno/síntese química , Derivados de Benzeno/farmacologia , Inibidores de Histona Desacetilases , Modelos Moleculares , Derivados de Benzeno/química , Sítios de Ligação/efeitos dos fármacos , Histona Desacetilase 1 , Histona Desacetilase 2 , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Estrutura Molecular , Isoformas de Proteínas , Proteínas Repressoras , Relação Estrutura-AtividadeRESUMO
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.