ABSTRACT
Starting from potent inhibitors of PI3Kα having poor general kinase selectivity (e.g., 1 and 2), optimisation of this series led to the identification of 25, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ, selective versus PI3Kß and PI3Kγ, with excellent general kinase selectivity. Compound 25 displayed low metabolic turnover and suitable physical properties for oral administration. In vivo, compound 25 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kα mutated SKOV-3 xenograft tumour model after chronic oral administration at 25mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials.
Subject(s)
Antineoplastic Agents/pharmacology , Oxadiazoles/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Dogs , Humans , Mice , Mice, Nude , Mice, SCID , Molecular Docking Simulation , Oxadiazoles/chemical synthesis , Piperidines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Rats , Xenograft Model Antitumor AssaysABSTRACT
A new series of quinoline ether inhibitors, which potently and selectively inhibit PDGFR tyrosine kinases, is described in this Letter. Compounds 23 and 33 are selective, low nanomolar inhibitors of PDGFRα and ß, display good pharmacokinetics in rat and dog and are active in vivo at low doses when given orally twice daily. Further evaluation of these compounds is warranted.
Subject(s)
Ethers/pharmacology , Quinolines/pharmacology , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Animals , Dogs , Dose-Response Relationship, Drug , Drug Discovery , Protein-Tyrosine Kinases/antagonists & inhibitors , RatsABSTRACT
A new series of Quinazoline Ether Inhibitor which potently inhibits VEGFR-2 and PDGFR tyrosine kinases is described here. In vitro, pharmacokinetics and in vivo evaluations led to the selection of AZD2932.
Subject(s)
Ethers/chemical synthesis , Ethers/pharmacology , Quinazolines/chemical synthesis , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Algorithms , Animals , Chemistry, Pharmaceutical/methods , Dogs , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Female , Humans , Inhibitory Concentration 50 , Male , Models, Chemical , Phosphorylation , Quinazolines/pharmacology , RatsABSTRACT
A new class of 1-acetanilide-4-aminopyrazole-substituted quinazoline Aurora kinase inhibitors has been discovered possessing highly potent cellular activity. Continuous infusion into athymic mice bearing SW620 tumors of the soluble phosphate derivative 2 led to dose-proportional exposure of the des-phosphate compound 8 with a high-unbound fraction. The combination of potent cell activity and high free-drug exposure led to pharmacodynamic changes in the tumor at low doses, indicative of Aurora B-kinase inhibition and a reduction in tumor volume.
Subject(s)
Colonic Neoplasms/drug therapy , Protein Kinase Inhibitors/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemistry , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Animals , Aurora Kinase B , Aurora Kinases , Cell Cycle/drug effects , Colonic Neoplasms/enzymology , Colonic Neoplasms/pathology , Cytochrome P-450 CYP3A/metabolism , Electrophysiology , Ether-A-Go-Go Potassium Channels/metabolism , Histones/metabolism , Humans , Male , Mice , Mice, Nude , Molecular Structure , Phosphorylation/drug effects , Protein Serine-Threonine Kinases/metabolism , Quinazolines/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.
Subject(s)
Antineoplastic Agents/chemical synthesis , Organophosphates/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemical synthesis , Quinazolines/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Aurora Kinase A , Aurora Kinase B , Aurora Kinases , Cell Division/drug effects , Cell Line, Tumor , Cytochrome P-450 Enzyme Inhibitors , Drug Screening Assays, Antitumor , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/drug effects , Female , Histones/metabolism , Humans , Male , Mice , Mice, Nude , Organophosphates/pharmacokinetics , Organophosphates/pharmacology , Phosphorylation , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Protein Binding , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , Rats , Recombinant Proteins/antagonists & inhibitors , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate that quinazolines with a substituted aminothiazole at C4 possess potent Aurora A and B inhibitory activity and excellent selectivity against a panel of various serine-threonine and tyrosine kinases, as exemplified by compound 46. We found also that the position and nature of the substituent on the thiazole play key roles in cellular potency. Compounds with an acetanilide substituent at C5' have the greatest cellular activity. The importance of the C5' position for substitution has been rationalized by ab initio molecular orbital calculations. Results show that the planar conformation with the sulfur of the thiazole next to the quinazoline N-3 is strongly favored over the other possible planar conformation. Compound 46 is a potent suppressor of the expression of phospho-histone H3 in tumor cells in vitro as well as in vivo, where 46, administered as its phosphate prodrug 54, suppresses the expression of phospho-histone H3 in subcutaneously implanted tumors in nude mice.
