ROCK inhibitors 2. Improving potency, selectivity and solubility through the application of rationally designed solubilizing groups

Huai Gao; Craig Marhefka; Marc D Jacobs; Jingrong Cao; Upul K Bandarage; Jeremy Green

doi:10.1016/j.bmcl.2018.06.043

ROCK inhibitors 2. Improving potency, selectivity and solubility through the application of rationally designed solubilizing groups

Bioorg Med Chem Lett. 2018 Aug 15;28(15):2616-2621. doi: 10.1016/j.bmcl.2018.06.043. Epub 2018 Jun 21.

Authors

Huai Gao¹, Craig Marhefka¹, Marc D Jacobs¹, Jingrong Cao¹, Upul K Bandarage¹, Jeremy Green²

Affiliations

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

PMID: 29945794
DOI: 10.1016/j.bmcl.2018.06.043

Abstract

Solubilizing groups have been frequently appended to kinase inhibitor drug molecules when solubility is insufficient for pharmaceutical development. Such groups are usually located at substitution sites that have minimal impact on target activity. In this report we describe the incorporation of solubilizing groups in a class of Rho kinase (ROCK) inhibitors that not only confer improved solubility, but also enhance target potency and selectivity against a closely related kinase, PKA.

Keywords: ROCK; Rho kinase; Solubilizing group; Structure-based design.

MeSH terms

Binding Sites
Crystallography, X-Ray
Drug Design*
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Solubility
rho-Associated Kinases / antagonists & inhibitors*
rho-Associated Kinases / chemistry

Substances

Protein Kinase Inhibitors
rho-Associated Kinases