ABSTRACT
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
The optimization of imidazo[1,2-a]pyridine inhibitors as potent and selective inhibitors of IGF-1R is presented. Further optimization of oral exposure in mice is also discussed. Detailed selectivity, in vitro activity, and in vivo PK profiles of an optimized compound is also highlighted.
Subject(s)
Chemistry, Pharmaceutical/methods , Pyridines/chemistry , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, IGF Type 1/chemistry , Administration, Oral , Aniline Compounds/chemistry , Animals , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Molecular Conformation , Pyridines/chemical synthesis , Pyridines/pharmacology , Receptor, Insulin/metabolismABSTRACT
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
[reaction: see text] The first examples of free radical-mediated vinyl amination are described by nonconventional vinyl radical addition to azomethine nitrogen. This new vinyl amination protocol is mild and provides convenient synthetic access to nonstabilized N,N-dialkyl enamines and tandem bond-forming processes.
Subject(s)
Free Radicals/chemistry , Heterocyclic Compounds/chemistry , Amination , Magnetic Resonance Spectroscopy , Molecular StructureABSTRACT
A series of dianilinopyrimidineureas demonstrate potency as VEGFR2 kinase inhibitors.