Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Bioorg Med Chem Lett ; 22(15): 4979-85, 2012 Aug 01.
Article in English | MEDLINE | ID: mdl-22765894

ABSTRACT

Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models.


Subject(s)
Drug Design , Indoles/chemical synthesis , Piperidines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Cytochrome P-450 CYP3A/metabolism , Female , Half-Life , Humans , Indoles/pharmacokinetics , Indoles/therapeutic use , Lung/drug effects , Lung/metabolism , Mice , Neoplasms/drug therapy , Piperidines/pharmacokinetics , Piperidines/therapeutic use , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Rats , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship , Transplantation, Heterologous
2.
Bioorg Med Chem Lett ; 22(11): 3732-8, 2012 Jun 01.
Article in English | MEDLINE | ID: mdl-22542012

ABSTRACT

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 Relationship
3.
Bioorg Med Chem Lett ; 22(11): 3727-31, 2012 Jun 01.
Article in English | MEDLINE | ID: mdl-22560567

ABSTRACT

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.


Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidinones/chemistry , Pyrimidinones/pharmacokinetics , Animals , Binding Sites , Cell Cycle Checkpoints/drug effects , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Computer Simulation , Humans , Mice , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Pyrimidinones/therapeutic use , Rats , Structure-Activity Relationship , Transplantation, Heterologous , Up-Regulation
SELECTION OF CITATIONS
SEARCH DETAIL
...