Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 2. Probing the indeno ring substituent pattern

David A Nugiel; Anup Vidwans; Anna-Marie Etzkorn; Karen A Rossi; Pamela A Benfield; Catherine R Burton; Sarah Cox; Deborah Doleniak; Steven P Seitz

doi:10.1021/jm020171+

Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 2. Probing the indeno ring substituent pattern

J Med Chem. 2002 Nov 21;45(24):5224-32. doi: 10.1021/jm020171+.

Authors

David A Nugiel¹, Anup Vidwans, Anna-Marie Etzkorn, Karen A Rossi, Pamela A Benfield, Catherine R Burton, Sarah Cox, Deborah Doleniak, Steven P Seitz

Affiliation

¹ Bristol-Myers Squibb Company, Box 80336, Wilmington, Delaware 19880-0336, USA. [email protected]

PMID: 12431050
DOI: 10.1021/jm020171+

Abstract

We disclose a novel series of indenopyrazole-based cyclin-dependent kinase (CDK) inhibitors. Kinetic experiments confirmed our initial molecular modeling studies that the compounds are competitive with respect to adenosine 5'-triphosphate (ATP) and bind in the kinase ATP pocket. A unique combination of active pharmacophores led us to a series of semicarbazide-based inhibitors that are highly potent against CDK2 and CDK4 while maintaining selectivity against other relevant serine/threonine kinases. These compounds were active against a transformed human colon cancer cell line (HCT116) while maintaining an acceptable margin of activity against a normal fibroblast cell line. The compounds were found to be highly protein bound in our cell-based assay with the exception of 11k, which maintained a reasonable level of activity in the presence of human plasma proteins.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology
Antineoplastic Agents / toxicity
Blood Proteins / metabolism
CDC2-CDC28 Kinases*
Cell Division / drug effects
Cell Line
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinases / antagonists & inhibitors*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / toxicity
Humans
Kinetics
Models, Molecular
Morpholines / chemical synthesis*
Morpholines / chemistry
Morpholines / pharmacology
Protein Binding
Protein Serine-Threonine Kinases / antagonists & inhibitors
Proto-Oncogene Proteins*
Pyrazoles / chemical synthesis*
Pyrazoles / chemistry
Pyrazoles / pharmacology
Pyrazoles / toxicity
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

3-(4-methoxyphenyl)-5-(morpholinylcarbamoyl)aminoindeno(1,2-c)pyrazol-4-one
Antineoplastic Agents
Blood Proteins
Enzyme Inhibitors
Morpholines
Proto-Oncogene Proteins
Pyrazoles
Protein Serine-Threonine Kinases
CDC2-CDC28 Kinases
CDK2 protein, human
CDK4 protein, human
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinases