ABSTRACT
A series of naphthyridine and naphthyridinone allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been optimized to have potent dual activity against the activated kinase as well as the activation of Akt in cells. One molecule in particular, compound 17, has potent inhibitory activity against Akt1 and 2 in vivo in a mouse lung and efficacy in a tumor xenograft model.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Naphthyridines/chemical synthesis , Naphthyridines/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Combinatorial Chemistry Techniques , Disease Models, Animal , Drug Design , Drug Screening Assays, Antitumor , Humans , Mice , Naphthyridines/chemistry , Proto-Oncogene Proteins c-akt/metabolism , Structure-Activity RelationshipABSTRACT
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
3,7-Diarylsubstituted imidazopyridines were designed and developed as a new class of KDR kinase inhibitors. A variety of imidazopyridines were synthesized and potent inhibitors of KDR kinase activity were identified with good aqueous solubility.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Drug Design , Humans , Molecular Structure , Solubility , 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).
