ABSTRACT
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).
Subject(s)
Morpholines/pharmacology , Multiprotein Complexes/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Benzamides , Cell Growth Processes/drug effects , Cells, Cultured , Hepatocytes/drug effects , Hepatocytes/enzymology , Hepatocytes/metabolism , Humans , Mechanistic Target of Rapamycin Complex 1 , Mechanistic Target of Rapamycin Complex 2 , PyrimidinesABSTRACT
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of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1H-quinolin-4-ones.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.
Subject(s)
Benzopyrans/chemistry , DNA-Activated Protein Kinase/antagonists & inhibitors , Pyridines/chemical synthesis , Pyrimidinones/chemical synthesis , Quinolones/chemical synthesis , Cell Membrane Permeability , DNA Damage/drug effects , DNA Damage/radiation effects , Furans/chemical synthesis , Furans/chemistry , Furans/pharmacology , HeLa Cells , Humans , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Quinolones/chemistry , Quinolones/pharmacology , Small Molecule Libraries , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , Diamines/chemistry , Morpholines/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinases/chemistry , Pyrimidines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line , Diamines/chemical synthesis , Diamines/pharmacology , Drug Discovery , Humans , Mechanistic Target of Rapamycin Complex 1 , Morpholines/chemical synthesis , Morpholines/pharmacology , Multiprotein Complexes , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Proteins , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity Relationship , TOR Serine-Threonine Kinases , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolismABSTRACT
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.
ABSTRACT
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.
