RESUMEN
The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC(50), led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21).
Asunto(s)
Morfolinas/farmacología , Complejos Multiproteicos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Benzamidas , Procesos de Crecimiento Celular/efectos de los fármacos , Células Cultivadas , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Hepatocitos/metabolismo , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , PirimidinasRESUMEN
We describe a novel series of potent inhibitors of the kinase activity of mTOR. The compounds display good selectivity relative to other PI3K-related kinase family members and, in cellular assays, inhibit both mTORC1 and mTORC2 complexes and exhibit good antiproliferative activity.
Asunto(s)
Antineoplásicos/química , Diaminas/química , Morfolinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/química , Pirimidinas/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular , Diaminas/síntesis química , Diaminas/farmacología , Descubrimiento de Drogas , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Morfolinas/síntesis química , Morfolinas/farmacología , Complejos Multiproteicos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Proteínas , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) ( Leahy , J. J. J. ; Golding , B. T. ; Griffin , R. J. ; Hardcastle , I. R. ; Richardson , C. ; Rigoreau , L. ; Smith , G. C. M. Bioorg. Med. Chem. Lett. 2004 , 14 , 6083 - 6087) as a potent inhibitor (IC50 = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH2)(n)NR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines (e.g., morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki-Miyaura cross-coupling. Potent DNA-PK inhibitory activity was generally observed across the compound series, with structure-activity studies indicating that optimal potency resided in pyridopyrimidin-4-ones bearing a substituted dibenzothiophen-4-yl group. Several of the newly synthesized compounds (e.g., 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzothiophen-1-yl]acetamide) combined high potency against the target enzyme (DNA-PK IC50 = 8 nM) with promising activity as potentiators of ionizing radiation-induced cytotoxicity in vitro.
Asunto(s)
Benzopiranos/química , Proteína Quinasa Activada por ADN/antagonistas & inhibidores , Piridinas/síntesis química , Pirimidinonas/síntesis química , Quinolonas/síntesis química , Permeabilidad de la Membrana Celular , Daño del ADN/efectos de los fármacos , Daño del ADN/efectos de la radiación , Furanos/síntesis química , Furanos/química , Furanos/farmacología , Células HeLa , Humanos , Piridinas/química , Piridinas/farmacología , Pirimidinonas/química , Pirimidinonas/farmacología , Quinolonas/química , Quinolonas/farmacología , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
The 5/7-, 5/8- and 5/9-bicyclic lactams 3, 17, 5 and 6 have been synthesised as single diastereoisomers by a route involving ring closing olefin metathesis. The X-ray crystal structure of the amino acid hydrochloride has been carried out and compared to that of the saturated external beta-turn constraint 18.
RESUMEN
A new method for gamma-acylation of protected glutamic acids, involving intramolecular rearrangement of an acyl urethane, has been devised to prepare the protected gamma-carboxyglutamates 7, 9 and 11 and the protected 4-acylglutamates 15 and 22 from N,N-bisurethanes or N-acyl-N-urethanes of general structure 1. When the formyl-urethane 17 was used in the reaction, then the intermediate 18 in the intramolecular rearrangement was obtained.