RESUMEN
Caspases are a family of cysteine-dependent proteases with important cellular functions in inflammation and apoptosis, while also implicated in human diseases. Classical chemical tools to study caspase functions lack selectivity for specific caspase family members due to highly conserved active sites and catalytic machinery. To overcome this limitation, we targeted a non-catalytic cysteine residue (C264) unique to caspase-6 (C6), an enigmatic and understudied caspase isoform. Starting from disulfide ligands identified in a cysteine trapping screen, we used a structure-informed covalent ligand design to produce potent, irreversible inhibitors (3a) and chemoproteomic probes (13-t) of C6 that exhibit unprecedented selectivity over other caspase family members and high proteome selectivity. This approach and the new tools described will enable rigorous interrogation of the role of caspase-6 in developmental biology and in inflammatory and neurodegenerative diseases.
Asunto(s)
Caspasas , Cisteína , Humanos , Caspasa 6 , Apoptosis , Inhibidores de Cisteína Proteinasa/farmacologíaRESUMEN
The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar substituents provided improvements in the compound's in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Cromanos/química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Sitios de Unión , Células Cultivadas , Etilaminas/síntesis química , Etilaminas/química , Etilaminas/farmacología , Concentración 50 Inhibidora , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
The synthesis and in vivo SAR of 2-(2,2,2)-trifluoroethyl-benzimidazoles are described. Prostate antagonism and/or levator ani agonism can be modulated by varying the substitution at the 2-position of 5,6-dichloro-benzimidazoles. Potent androgen agonists on the muscle were discovered that strongly bind to the androgen receptor (2-17 nM) and show potent in vivo efficacy (0.03-0.11 mg/day). True SARMs showing both prostate antagonism and levator ani agonism were revealed.
Asunto(s)
Bencimidazoles/síntesis química , Receptores Androgénicos/efectos de los fármacos , Antagonistas de Receptores Androgénicos , Andrógenos , Animales , Bencimidazoles/agonistas , Bencimidazoles/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Indicadores y Reactivos , Masculino , Modelos Moleculares , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Próstata/efectos de los fármacos , Próstata/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The synthesis and in vivo SAR of 5,6-dichloro-benzimidazole derivatives as novel selective androgen receptor antagonists are described. During screening of 2-alkyl benzimidazoles, it was found that a trifluoromethyl group greatly enhances antagonist activity in the prostate. Benzimidazole 1 is a potent AR antagonist in the rat prostate (ID50 = 0.15 mg/day).
Asunto(s)
Antagonistas de Andrógenos/síntesis química , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores Androgénicos , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Animales , Indicadores y Reactivos , Masculino , Peso Molecular , Orquiectomía , Próstata/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfuros/síntesis química , Sulfonas/síntesis químicaRESUMEN
The synthesis and in vivo SAR of N-benzyl, N-aceto, and N-ethylene ether derivatives of 2-(2,2,2-trifluoroethyl)-5,6-dichloro-benzimidazole as novel androgen receptor antagonists are described. SAR studies led to the discovery of 4-bromo-benzyl benzimidazole 17 as a more potent androgen receptor antagonist in the rat prostate (ID(50)=0.13mg/day), compared with bicalutamide (ID(50)=0.23mg/day).