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 novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.
Subject(s)
Antineoplastic Agents/chemistry , ErbB Receptors/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrrolidines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Animals , Mice , Pharmacokinetics , Pyrimidines/chemical synthesis , Pyrrolidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
A novel class of substituted pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines has been identified that are potent and selective inhibitors of both EGFR/ErbB-2 receptor tyrosine kinases. The inhibitors are found to display a range of enzyme and cellular potency and also to display a varying level of covalent modification of the kinase targets. Selected molecules, including compound 15h, were found to be potent in enzymatic and cellular assays while also demonstrating exposure in the mouse from an oral dose.