Pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides as novel anti-proliferative agents: parallel synthesis for lead optimization of amide region

Ariamala Gopalsamy; Hui Yang; John W Ellingboe; Hwei-Ru Tsou; Nan Zhang; Erick Honores; Dennis Powell; Miriam Miranda; John P McGinnis; Sridhar K Rabindran

doi:10.1016/j.bmcl.2005.01.066

Pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides as novel anti-proliferative agents: parallel synthesis for lead optimization of amide region

Bioorg Med Chem Lett. 2005 Mar 15;15(6):1591-4. doi: 10.1016/j.bmcl.2005.01.066.

Authors

Ariamala Gopalsamy¹, Hui Yang, John W Ellingboe, Hwei-Ru Tsou, Nan Zhang, Erick Honores, Dennis Powell, Miriam Miranda, John P McGinnis, Sridhar K Rabindran

Affiliation

¹ Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA. [email protected]

PMID: 15745803
DOI: 10.1016/j.bmcl.2005.01.066

Abstract

A novel series of p21 chemoselective agents containing a pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides were identified by high throughput screening. Optimization of the amide region by parallel synthesis and the iterative design toward understanding structure-activity relationship to improve potency are described. The isopropyl carbamate derivative 34 was identified as a highly chemoselective agent displaying a potency of 51 nM in the p21 deficient cell line.

MeSH terms

Amides / chemical synthesis*
Amides / pharmacology*
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology*
Cell Cycle Proteins / physiology
Cell Proliferation / drug effects
Cyclin-Dependent Kinase Inhibitor p21
HCT116 Cells
Humans
Inhibitory Concentration 50
Models, Chemical
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / pharmacology
Pyrimidines / chemical synthesis
Pyrimidines / pharmacology
Structure-Activity Relationship

Substances

Amides
Antineoplastic Agents
CDKN1A protein, human
Cell Cycle Proteins
Cyclin-Dependent Kinase Inhibitor p21
Pyrazoles
Pyrimidines