ABSTRACT
A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.
Subject(s)
Aminopyridines/chemical synthesis , Potassium Channels, Voltage-Gated/metabolism , Pyridines/chemical synthesis , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Thiazoles/chemical synthesis , Administration, Oral , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Biological Availability , Cell Line , Dogs , ERG1 Potassium Channel , Electrocardiography/drug effects , Ether-A-Go-Go Potassium Channels , In Vitro Techniques , Lung/enzymology , Macaca mulatta , Male , Mice , Microsomes, Liver/metabolism , Phosphorylation , Pyridines/pharmacokinetics , Pyridines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Tissue Distribution , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
An azo-dye lead was modified to a novel N-(1,3-thiazol-2-yl)pyridin-2-amine series of KDR kinase inhibitors through the use of rapid analog libraries. This new class has been found to be potent, selective, and of low molecular weight. Molecular modeling has postulated an interesting conformational preference and binding mode for these compounds in the active site of the enzyme.
Subject(s)
Amines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Amines/chemical synthesis , Binding Sites , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Models, Molecular , Protein Binding , Protein Conformation/drug effects , Structure-Activity Relationship , Thermodynamics , Vascular Endothelial Growth Factor Receptor-2/chemistryABSTRACT
Small molecule inhibitors of KDR kinase activity have typically possessed poor intrinsic physical properties including low aqueous solubility and high lipophilicity. These features have often conferred limited cell permeability manifested in low levels of cell-based KDR inhibitory activity and oral bioavailability. Thus, the design of inhibitors with appropriate physical properties has played a critical role in the development of clinical candidates. We present a variety of structural modifications that have afforded improvements in physical properties and thereby have addressed suboptimal cellular potency and pharmacokinetics for three unique classes of KDR kinase inhibitors.
Subject(s)
Drug Design , Enzyme Inhibitors/chemistry , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Binding Sites , Biological Availability , Cell Membrane Permeability , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Models, Molecular , Molecular Structure , Solubility , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/chemistryABSTRACT
Modifications to the basic side-chain of early lead structures of the indolyl quinolinone class of KDR kinase inhibitors resulted in improved pharmacokinetic and ancillary profiles. Specifically, compounds bearing 5-amido- and 5-sulphonamido-indolyl substituents exhibited lower plasma clearance and weaker binding affinity for the I(Kr) potassium channel hERG.
Subject(s)
Cation Transport Proteins/metabolism , Enzyme Inhibitors/pharmacokinetics , Potassium Channels, Voltage-Gated , Potassium Channels/metabolism , Quinolones/pharmacokinetics , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Cell Line , Dogs , Enzyme Inhibitors/chemistry , Ether-A-Go-Go Potassium Channels , Humans , Microsomes, Liver/enzymology , Protein Binding/physiology , Quinolones/chemistry , Rats , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
We have discovered 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as potent inhibitors of KDR kinase activity. This communication details the evolution of this novel class from a potent screening lead of vastly different structure with an emphasis on structural modifications that retained activity and provided improvements in key physical properties. The synthesis and in-depth evaluation of these inhibitors are described.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Indoles/chemical synthesis , Indoles/pharmacokinetics , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/pharmacology , Animals , Biological Availability , Cell Line , Half-Life , Indoles/pharmacology , Inhibitory Concentration 50 , Rats , Structure-Activity RelationshipABSTRACT
1,5-Diarylbenzimidazoles have been identified as potent inhibitors of KDR kinase activity. The series was developed with a goal of finding compounds with optimal drug-like properties. This communication describes structural modifications in the series that enhance solubility, lower protein binding, and provide compounds with excellent potency and pharmacokinetic profiles.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Chemical Phenomena , Chemistry, Physical , Dogs , Drug Design , Enzyme Inhibitors/pharmacokinetics , Half-Life , Hydrogen-Ion Concentration , Indicators and Reagents , Molecular Conformation , Rats , Structure-Activity RelationshipABSTRACT
2,4-Disubstituted pyrimidines were synthesized as a novel class of KDR kinase inhibitors. Evaluation of the SAR of the screening lead compound 1 (KDR IC(50)=105 nM, Cell IC(50)=8% inhibition at 500 nM) led to the potent 3,5-dimethylaniline derivative 2d (KDR IC(50)=6 nM, cell IC(50)=19 nM).
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Pyrimidines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cells, Cultured , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Pyrimidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
We have introduced solubilizing functionality to a 3,6-disubstituted pyrazolo[1,5-a]pyrimidine series of KDR kinase inhibitors to improve the physical properties of these compounds. The addition of a basic side-chain to the 6-aryl ring, introduction of 3-pyridyl groups, and most significantly, incorporation of a 4-pyridinonyl substituent at the 6-position of the core are modifications that maintain and often enhance the intrinsic potency of this class of inhibitors. Moreover, the improvements in physical properties result in marked increases in cellular activity and more favorable pharmacokinetics in rats. The synthesis and SAR of these compounds are described.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Pyrimidines/pharmacokinetics , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/pharmacology , Animals , Cell Division/drug effects , Cell Line , Endothelium, Vascular/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Metabolic Clearance Rate , Pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Rats , Solubility , Structure-Activity RelationshipABSTRACT
We have synthesized and evaluated the activity of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines as a new class of KDR kinase inhibitors. Starting with screening lead 1, potency against isolated KDR was fully optimized with 3-thienyl and 4-methoxyphenyl substituents at the 6- and 3-positions (3g, KDR IC(50)=19 nM), respectively. The synthesis and SAR of these compounds are described.