RESUMEN
Compound 1 (SNS-314) is a potent and selective Aurora kinase inhibitor that is currently in clinical trials in patients with advanced solid tumors. This communication describes the synthesis of prodrug derivatives of 1 with improved aqueous solubility profiles. In particular, phosphonooxymethyl-derived prodrug 2g has significantly enhanced solubility and is converted to the biologically active parent (1) following iv as well as po administration to rodents.
Asunto(s)
Compuestos de Fenilurea/química , Profármacos/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Tiazoles/química , Agua/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Aurora Quinasas , Masculino , Ratones , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Profármacos/farmacocinética , Profármacos/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Solubilidad , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.
Asunto(s)
Antineoplásicos/química , Bencimidazoles/química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Aurora Quinasas , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Línea Celular Tumoral , Humanos , Ratones , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.
Asunto(s)
Neoplasias Experimentales/tratamiento farmacológico , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinazolinas/farmacología , Tiazoles/química , Tiazoles/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Aurora Quinasas , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Ratones , Trasplante de Neoplasias , Neoplasias Experimentales/enzimología , Quinazolinas/química , Relación Estructura-ActividadRESUMEN
The design, synthesis, and in vitro activities of a series of potent and selective small-molecule inhibitors of caspase-3 are described. From extended tethering, a salicylic acid fragment was identified as having binding affinity for the S(4) pocket of caspase-3. X-ray crystallography and molecular modeling of the initial tethering hit resulted in the synthesis of 4, which reversibly inhibited caspase-3 with a K(i) = 40 nM. Further optimization led to the identification of a series of potent and selective inhibitors with K(i) values in the 20-50 nM range. One of the most potent compounds in this series, 66b, inhibited caspase-3 with a K(i) = 20 nM and selectivity of 8-500-fold for caspase-3 vs a panel of seven caspases (1, 2, and 4-8). A high-resolution X-ray cocrystal structure of 4 and 66b supports the predicted binding modes of our compounds with caspase-3.
Asunto(s)
Ácido Aspártico/síntesis química , Inhibidores de Caspasas , Inhibidores Enzimáticos/síntesis química , Salicilatos/síntesis química , Sulfonamidas/síntesis química , Ácido Aspártico/análogos & derivados , Ácido Aspártico/química , Benzoxazoles/síntesis química , Benzoxazoles/química , Sitios de Unión , Caspasa 3 , Caspasas/química , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/química , Fluorenos/síntesis química , Fluorenos/química , Humanos , Unión Proteica , Salicilatos/química , Sulfonamidas/química , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
The design and synthesis of a series of novel, reversible, small molecule inhibitors of caspase-3 are described.