ABSTRACT
The development and application of high-load, recyclable magnetic Co/C hybrid ROMP-derived benzenesulfonyl chloride and analogues is reported. The regeneration and utility of these reagents in the methylation/alkylation of various carboxylic acids is demonstrated via efficient retrieval of the magnetic reagent with a neodymium magnet. Additional reactions employing the analogue sulfonic acid and in situ generated magnetic benzenesulfonyl azide are also reported.
Subject(s)
Carbon/chemistry , Cobalt/chemistry , Magnetite Nanoparticles/chemistry , Sulfones/chemical synthesis , Alkylation , Carboxylic Acids/chemistry , Indicators and Reagents , Particle Size , Surface PropertiesABSTRACT
We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.
Subject(s)
Antineoplastic Agents/pharmacology , Janus Kinase 2/antagonists & inhibitors , Neoplasms, Experimental/drug therapy , Proline/analogs & derivatives , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Crystallography, X-Ray , Dogs , Dose-Response Relationship, Drug , Haplorhini , High-Throughput Screening Assays , Janus Kinase 2/metabolism , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Neoplasms, Experimental/pathology , Proline/administration & dosage , Proline/chemistry , Proline/pharmacology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure.
Subject(s)
Drug Design , Furans/chemistry , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Pyrimidinones/chemistry , Binding Sites , Computer Simulation , Crystallography, X-Ray , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Proto-Oncogene Proteins c-pim-1/metabolism , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Structure-Activity RelationshipABSTRACT
CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.
