Design, synthesis and SAR of thienopyridines as potent CHK1 inhibitors

Lianyun Zhao; Yingxin Zhang; Chaoyang Dai; Timothy Guzi; Derek Wiswell; Wolfgang Seghezzi; David Parry; Thierry Fischmann; M Arshad Siddiqui

doi:10.1016/j.bmcl.2010.10.105

Design, synthesis and SAR of thienopyridines as potent CHK1 inhibitors

Bioorg Med Chem Lett. 2010 Dec 15;20(24):7216-21. doi: 10.1016/j.bmcl.2010.10.105. Epub 2010 Oct 26.

Authors

Lianyun Zhao¹, Yingxin Zhang, Chaoyang Dai, Timothy Guzi, Derek Wiswell, Wolfgang Seghezzi, David Parry, Thierry Fischmann, M Arshad Siddiqui

Affiliation

¹ Department of Chemistry, Merck Research Laboratories, Cambridge, MA 02141, USA. lianyun.zhao@merck.com

PMID: 21074424
DOI: 10.1016/j.bmcl.2010.10.105

Abstract

A novel series of CHK1 inhibitors based on thienopyridine template has been designed and synthesized. These inhibitors maintain critical hydrogen bonding with the hinge and conserved water in the ATP binding site. Several compounds show single digit nanomolar CHK1 activities. Compound 70 shows excellent enzymatic activity of 1 nM.

MeSH terms

Adenosine Triphosphate / chemistry
Binding Sites
Checkpoint Kinase 1
Crystallography, X-Ray
Drug Design
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Protein Kinases / chemistry*
Protein Kinases / metabolism
Pyridazines / chemical synthesis*
Pyridazines / chemistry
Pyridazines / pharmacology
Structure-Activity Relationship
Thienopyridines / chemical synthesis
Thienopyridines / chemistry*
Thienopyridines / pharmacology
Thiophenes / chemical synthesis*
Thiophenes / chemistry
Thiophenes / pharmacology

Substances

Protein Kinase Inhibitors
Pyridazines
Thienopyridines
Thiophenes
Adenosine Triphosphate
Protein Kinases
Checkpoint Kinase 1