Potency switch between CHK1 and MK2: discovery of imidazo[1,2-a]pyrazine- and imidazo[1,2-c]pyrimidine-based kinase inhibitors

Zhaoyang Meng; Jeffrey P Ciavarri; Andrew McRiner; Yinyan Zhao; Lianyun Zhao; Panduranga Adulla Reddy; Xingmin Zhang; Thierry O Fischmann; Charles Whitehurst; M Arshad Siddiqui

doi:10.1016/j.bmcl.2013.03.100

Potency switch between CHK1 and MK2: discovery of imidazo[1,2-a]pyrazine- and imidazo[1,2-c]pyrimidine-based kinase inhibitors

Bioorg Med Chem Lett. 2013 May 15;23(10):2863-7. doi: 10.1016/j.bmcl.2013.03.100. Epub 2013 Apr 4.

Authors

Zhaoyang Meng¹, Jeffrey P Ciavarri, Andrew McRiner, Yinyan Zhao, Lianyun Zhao, Panduranga Adulla Reddy, Xingmin Zhang, Thierry O Fischmann, Charles Whitehurst, M Arshad Siddiqui

Affiliation

¹ Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA. zhaoyang.meng@merck.com

PMID: 23587425
DOI: 10.1016/j.bmcl.2013.03.100

Abstract

Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and MK2.

MeSH terms

Checkpoint Kinase 1
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / metabolism
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Kinases / metabolism*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Pyrazines / chemical synthesis
Pyrazines / chemistry
Pyrazines / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Imidazoles
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Pyrazines
Pyrimidines
imidazo(1,2-a)pyrazine
imidazo(1,2-c)pyrimidine
Protein Kinases
MAP-kinase-activated kinase 2
CHEK1 protein, human
Checkpoint Kinase 1
Protein Serine-Threonine Kinases