ROCK inhibitors 3: Design, synthesis and structure-activity relationships of 7-azaindole-based Rho kinase (ROCK) inhibitors

Upul K Bandarage; Jingrong Cao; Jon H Come; John J Court; Huai Gao; Marc D Jacobs; Craig Marhefka; Suganthi Nanthakumar; Jeremy Green

doi:10.1016/j.bmcl.2018.06.040

ROCK inhibitors 3: Design, synthesis and structure-activity relationships of 7-azaindole-based Rho kinase (ROCK) inhibitors

Bioorg Med Chem Lett. 2018 Aug 15;28(15):2622-2626. doi: 10.1016/j.bmcl.2018.06.040. Epub 2018 Jun 19.

Authors

Upul K Bandarage¹, Jingrong Cao², Jon H Come², John J Court², Huai Gao², Marc D Jacobs², Craig Marhefka², Suganthi Nanthakumar², Jeremy Green³

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.
³ Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, USA. Electronic address: jeremy_green@vrtx.com.

PMID: 30082069
DOI: 10.1016/j.bmcl.2018.06.040

Abstract

Rho kinase (ROCK) inhibitors are potential therapeutic agents for the treatment of a variety of disorders including hypertension, glaucoma and erectile dysfunction. Here we disclose a series of potent and selective ROCK inhibitors based on a substituted 7-azaindole scaffold. Substitution of the 3-position of 7-azaindole led to compounds such as 37, which possess excellent ROCK inhibitory potency and high selectivity against the closely related kinase PKA.

Keywords: 7-Azaindole; Lipophilic efficiency; ROCK; Rho kinase; Solubilizing group; Structure-based design.

MeSH terms

Crystallography, X-Ray
Drug Design*
Indoles / chemistry*
Ligands
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Solubility
Structure-Activity Relationship
rho-Associated Kinases / antagonists & inhibitors*

Substances

7-azaindole dimer
Indoles
Ligands
Protein Kinase Inhibitors
rho-Associated Kinases