ROCK inhibitors 4: Structure-activity relationship studies of 7-azaindole-based rho kinase (ROCK) inhibitors

Upul K Bandarage; John Court; Huai Gao; Suganthini Nanthakumar; Jon H Come; Simon Giroux; Jeremy Green

doi:10.1016/j.bmcl.2020.127721

ROCK inhibitors 4: Structure-activity relationship studies of 7-azaindole-based rho kinase (ROCK) inhibitors

Bioorg Med Chem Lett. 2021 Feb 1:33:127721. doi: 10.1016/j.bmcl.2020.127721. Epub 2020 Nov 28.

Authors

Upul K Bandarage¹, John Court², Huai Gao², Suganthini Nanthakumar², Jon H Come², Simon Giroux², Jeremy Green²

Affiliations

¹ Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA. Electronic address: upul_bandarage@vrtx.com.
² Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA.

PMID: 33259926
DOI: 10.1016/j.bmcl.2020.127721

Abstract

Rho kinase (ROCK) inhibitors are of therapeutic value for the treatment of disorders such as hypertension and glaucoma, and potentially of wider use against diseases such as cancer and multiple sclerosis. We previously reported a series of potent and selective ROCK inhibitors based on a substituted 7-azaindole scaffold. Here we extend the SAR exploration of the 7-azaindole series to identify leads for further evaluation. New compounds such as 16, 17, 19, 21 and 22 showed excellent ROCK potency and protein kinase A (PKA) selectivity, combined with microsome and hepatocyte stability.

Keywords: 7-Azaindole; Rho kinase (ROCK); Thiazole; protein kinase A (PKA).

MeSH terms

Animals
Dose-Response Relationship, Drug
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Rats
Structure-Activity Relationship
rho-Associated Kinases / antagonists & inhibitors*
rho-Associated Kinases / metabolism

Substances

7-azaindole dimer
Indoles
Protein Kinase Inhibitors
ROCK1 protein, human
rho-Associated Kinases