The discovery of tricyclic pyridone JAK2 inhibitors. Part 1: hit to lead

Tony Siu; Ekaterina S Kozina; Joon Jung; Craig Rosenstein; Anjili Mathur; Michael D Altman; Grace Chan; Lin Xu; Eric Bachman; Jan-Rung Mo; Melaney Bouthillette; Thomas Rush; Christopher J Dinsmore; C Gary Marshall; Jonathan R Young

doi:10.1016/j.bmcl.2010.10.031

The discovery of tricyclic pyridone JAK2 inhibitors. Part 1: hit to lead

Bioorg Med Chem Lett. 2010 Dec 15;20(24):7421-5. doi: 10.1016/j.bmcl.2010.10.031. Epub 2010 Oct 12.

Authors

Tony Siu¹, Ekaterina S Kozina, Joon Jung, Craig Rosenstein, Anjili Mathur, Michael D Altman, Grace Chan, Lin Xu, Eric Bachman, Jan-Rung Mo, Melaney Bouthillette, Thomas Rush, Christopher J Dinsmore, C Gary Marshall, Jonathan R Young

Affiliation

¹ Department of Chemistry, Merck & Co., Boston, MA 02115, USA. [email protected]

PMID: 21044843
DOI: 10.1016/j.bmcl.2010.10.031

Abstract

This paper describes the discovery and design of a novel class of JAK2 inhibitors. Furthermore, we detail the optimization of a screening hit using ligand binding efficiency and log D. These efforts led to the identification of compound 41, which demonstrates in vivo activity in our study.

MeSH terms

Animals
Binding Sites
Computer Simulation
Cyclization
Drug Evaluation, Preclinical
Heterocyclic Compounds, 3-Ring / chemical synthesis
Heterocyclic Compounds, 3-Ring / chemistry*
Heterocyclic Compounds, 3-Ring / pharmacology
Janus Kinase 2 / antagonists & inhibitors*
Janus Kinase 2 / metabolism
Mice
Mice, Inbred C57BL
Pyridones / chemical synthesis
Pyridones / chemistry*
Pyridones / pharmacology
STAT5 Transcription Factor / metabolism
Structure-Activity Relationship

Substances

Heterocyclic Compounds, 3-Ring
Pyridones
STAT5 Transcription Factor
Janus Kinase 2