Identification of 5H-chromeno[3,4-c]pyridine and 6H-isochromeno[3,4-c]pyridine derivatives as potent and selective dual ROCK inhibitors

Zilun Hu; Cailan Wang; Doree Sitkoff; Nathan L Cheadle; Songmei Xu; Jodi K Muckelbauer; Leonard P Adam; Ruth R Wexler; Mimi L Quan

doi:10.1016/j.bmcl.2020.127474

Identification of 5H-chromeno[3,4-c]pyridine and 6H-isochromeno[3,4-c]pyridine derivatives as potent and selective dual ROCK inhibitors

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127474. doi: 10.1016/j.bmcl.2020.127474. Epub 2020 Aug 15.

Authors

Zilun Hu¹, Cailan Wang², Doree Sitkoff², Nathan L Cheadle², Songmei Xu², Jodi K Muckelbauer², Leonard P Adam², Ruth R Wexler², Mimi L Quan²

Affiliations

¹ Research & Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, NJ 08543-5400, USA. Electronic address: zilun.hu@bms.com.
² Research & Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, NJ 08543-5400, USA.

PMID: 32805407
DOI: 10.1016/j.bmcl.2020.127474

Abstract

A novel series of 5H-chromeno[3,4-c]pyridine, 6H-isochromeno[3,4-c]pyridine and 6H-isochromeno[4,3-d]pyrimidine derivatives as dual ROCK1 and ROCK2 inhibitors is described. Optimization led to compounds with sub-nanomolar inhibitory affinity for both kinases and excellent kinome selectivity. Compound 19 exhibited ROCK1 and ROCK2 IC₅₀ of 0.67 nM and 0.18 nM respectively.

Keywords: Chromenopyridine; Chromenopyrimidine; ROCK inhibitor; Rho kinase.

MeSH terms

Crystallography, X-Ray
Dose-Response Relationship, Drug
Humans
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship
rho-Associated Kinases / antagonists & inhibitors*
rho-Associated Kinases / metabolism

Substances

Protein Kinase Inhibitors
Pyridines
ROCK1 protein, human
ROCK2 protein, human
rho-Associated Kinases