ABSTRACT
The synthesis of the title compounds was carried out by reacting dicarboxylic acid chlorides with oximes in the presence of excess triethylamine. Disubstituted malonyl chlorides gave 2-alkenyl-4,4-dialkyl-3,5-isoxazolidinediones (8a-f) and 2,2'-ethylidene-bis[4,4-dialkyl-3,5-isoxazolidinedione]s (9a-f). Compounds 9 were formed from 8 and its N-unsubstituted 3,5-isoxazolidinedione decomposition product. Phthaloyl chlorides reacted with acetone oxime to yield 3-(1-methylethenyl)-1H-2,3-benzoxazine-1,4(3H)-diones (16a-e). Products 16 spontaneously decomposed to give N-unsubstituted 1H-2,3-benzoxazine-1,4(3H)-diones (17a-e) at rates that were dependent on temperature and solvent. Kinetic studies showed that two of the compounds decomposed by zero-order kinetics under neutral conditions. Butanedioyl chloride did not produce a cyclic product.
Subject(s)
Benzoxazines/chemical synthesis , Chlorides/chemistry , Dicarboxylic Acids/chemistry , Oxazolidinones/chemical synthesis , Oximes/chemistry , Quinazolines/chemical synthesis , Benzoxazines/chemistry , Molecular Structure , Oxazolidinones/chemistry , Quinazolines/chemistryABSTRACT
Potent inhibitors of PLK1 with acceptable solubility, mouse iv clearance, and reduced CYP450 inhibition were identified. Drug-like properties were improved using a heteroaryl ring as a functional handle for manipulation of inhibitors' physiochemical and DMPK properties.
Subject(s)
Amides/chemistry , Antineoplastic Agents/chemistry , Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Binding Sites , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Computer Simulation , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Humans , Injections, Intravenous , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Structure-Activity Relationship , Thiophenes/chemistry , Polo-Like Kinase 1ABSTRACT
A series of thiophene PLK1 inhibitors was optimized for increased solubility and reduced protein binding through the appendage of basic amine functionality. Interesting selectivity between PLK1 and PLK3 was also obtained through these modifications.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Thiophenes/chemistry , Cell Cycle , Cell Cycle Proteins/chemistry , Cell Line, Tumor , Drug Design , Humans , Inhibitory Concentration 50 , Mitosis , Models, Chemical , Molecular Conformation , Protein Binding , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/chemistry , Proto-Oncogene Proteins/chemistry , Solubility , Tumor Suppressor Proteins , Polo-Like Kinase 1ABSTRACT
The discovery and development of a series of thiophenes as potent and selective inhibitors of PLK is described. Identification and characterization of 2, a useful in vitro PLK inhibitor tool compound, is also presented.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Thiophenes/antagonists & inhibitors , Animals , Cell Cycle , Cell Cycle Proteins/chemistry , Cell Line, Tumor , Cell Proliferation , Drug Design , Humans , Inhibitory Concentration 50 , Mice , Mitosis , Models, Chemical , Molecular Conformation , Protein Serine-Threonine Kinases/chemistry , Proto-Oncogene Proteins/chemistry , Thiophenes/chemistry , Polo-Like Kinase 1ABSTRACT
Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Cells, Cultured , Crystallography, X-Ray , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Humans , Indazoles , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Mice , Models, Molecular , Molecular Structure , Neoplasms/blood supply , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Receptors, Vascular Endothelial Growth Factor/chemistry , Receptors, Vascular Endothelial Growth Factor/metabolism , Sulfonamides/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
Optimization of P1-substituted pyrrolidinone based HIV protease inhibitors has yielded analogs with very potent antiviral activity.
