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.

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