Abstract
We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry*
-
Antineoplastic Agents / pharmacokinetics
-
Binding Sites
-
Cell Line, Tumor
-
Crystallography, X-Ray
-
Cyclin-Dependent Kinases / antagonists & inhibitors*
-
Cyclin-Dependent Kinases / metabolism
-
HCT116 Cells
-
Humans
-
Injections, Intravenous
-
Mice
-
Mice, Nude
-
Protein Kinase Inhibitors / chemical synthesis
-
Protein Kinase Inhibitors / chemistry*
-
Protein Kinase Inhibitors / pharmacokinetics
-
Pyrazoles / chemical synthesis
-
Pyrazoles / chemistry*
-
Pyrazoles / pharmacokinetics
-
Pyrroles / chemical synthesis
-
Pyrroles / chemistry*
-
Pyrroles / pharmacokinetics
-
Xenograft Model Antitumor Assays
Substances
-
Antineoplastic Agents
-
N-(6,6-dimethyl-5-((1-methylpiperidin-4-yl)carbonyl)-1,4,5,6-tetrahydropyrrolo(3,4-c)pyrazol-3-yl)-3-methylbutanamide
-
Protein Kinase Inhibitors
-
Pyrazoles
-
Pyrroles
-
Cyclin-Dependent Kinases