ABSTRACT
A series of novel 6-aminofuro[3,2-c]pyridines as kinase inhibitors is described, most notably, OSI-296 (6). We discuss our exploration of structure-activity relationships and optimization leading to OSI-296 and disclose its pharmacological activity against cMET and RON in cellular assays. OSI-296 is a potent and selective inhibitor of cMET and RON kinases that shows in vivo efficacy in tumor xenografts models upon oral dosing and is well tolerated.
Subject(s)
Antineoplastic Agents/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridines/chemistry , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , Female , Half-Life , Humans , Hydrogen-Ion Concentration , Mice , Mice, Nude , Mutation , Neoplasms/drug therapy , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
This Letter describes the medicinal chemistry effort towards a series of novel imidazo[1,5-a]pyrazine derived inhibitors of ACK1. Virtual screening led to the discovery of the initial hit, and subsequent exploration of structure-activity relationships and optimization of drug metabolism and pharmacokinetic properties led to the identification of potent, selective and orally bioavailable ACK1 inhibitors.
Subject(s)
Imidazoles/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazines/chemistry , Administration, Oral , Animals , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Structure-Activity RelationshipABSTRACT
This letter describes a series of small molecule inhibitors of IGF-1R with unique time-dependent binding kinetics and slow off-rates. Structure-activity and structure-kinetic relationships were elucidated and guided further optimizations within the series, culminating in compound 2. With an IGF-1R dissociative half-life (t 1/2) of >100 h, compound 2 demonstrated significant and extended PD effects in conjunction with tumor growth inhibition in xenograft models at a remarkably low and intermittent dose, which correlated with the observed in vitro slow off-rate properties.
ABSTRACT
This report describes the investigation of a series of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and optimization leading to the identification, characterization, and pharmacological activity of compound 9b, a potent, selective, well-tolerated, and orally bioavailable dual inhibitor of IGF-1R and IR with in vivo efficacy in tumor xenograft models, is discussed.
ABSTRACT
Self-assembled monolayers (SAMs) of glucose derivatives on gold have been prepared from alpha- and beta-glucopyranosylamide derivatives. The glucosyl conjugates were synthesized stereoselectively via the in situ generation of glucosyl isoxazolines followed by treatment with thiopyridyl esters. The resulting film structures were characterized by atomic force microscopy, reflection Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The experimental data indicated that alpha- or beta-linked glucopyranosylamide derivatives with free hydroxyl groups attach to gold via the thiol linker. Both derivatives form monolayer films with high packing densities--comparable to those typically observed for alkanethiol monolayers on gold. Acetate analogues of these conjugates do not form SAMs on gold; they form multilayered films under identical deposition conditions.
