3-Aryl-4-(arylhydrazono)-1H-pyrazol-5-ones: Highly ligand efficient and potent inhibitors of GSK3beta

Michael Arnost; Al Pierce; Ernst ter Haar; David Lauffer; Jaren Madden; Kirk Tanner; Jeremy Green

doi:10.1016/j.bmcl.2010.01.072

3-Aryl-4-(arylhydrazono)-1H-pyrazol-5-ones: Highly ligand efficient and potent inhibitors of GSK3beta

Bioorg Med Chem Lett. 2010 Mar 1;20(5):1661-4. doi: 10.1016/j.bmcl.2010.01.072. Epub 2010 Jan 21.

Authors

Michael Arnost¹, Al Pierce, Ernst ter Haar, David Lauffer, Jaren Madden, Kirk Tanner, Jeremy Green

Affiliation

¹ Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139, USA.

PMID: 20138514
DOI: 10.1016/j.bmcl.2010.01.072

Abstract

A series of 3-aryl-4-(arylhydrazono)-1H-pyrazol-5-one inhibitors of GSK3beta was developed from a low molecular weight, highly ligand efficient screening hit 1. Hit-to-lead optimization led to a number of highly potent inhibitors, while maintaining the high ligand efficiency of the screening hit.

MeSH terms

Binding Sites
Crystallography, X-Ray
Glycogen Synthase Kinase 3 / antagonists & inhibitors*
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Ligands*
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Protein Kinases / chemistry
Protein Kinases / metabolism
Pyrazolones / chemical synthesis
Pyrazolones / chemistry*
Pyrazolones / pharmacology
Structure-Activity Relationship

Substances

Ligands
Protein Kinase Inhibitors
Pyrazolones
Protein Kinases
Glycogen Synthase Kinase 3 beta
Glycogen Synthase Kinase 3