Design of Aminobenzothiazole Inhibitors of Rho Kinases 1 and 2 by Using Protein Kinase A as a Structure Surrogate

Chembiochem. 2018 Mar 16;19(6):613-621. doi: 10.1002/cbic.201700547. Epub 2018 Jan 30.

Abstract

We describe the design, synthesis, and structure-activity relationships (SARs) of a series of 2-aminobenzothiazole inhibitors of Rho kinases (ROCKs) 1 and 2, which were optimized to low nanomolar potencies by use of protein kinase A (PKA) as a structure surrogate to guide compound design. A subset of these molecules also showed robust activity in a cell-based myosin phosphatase assay and in a mechanical hyperalgesia in vivo pain model.

Keywords: benzothiazoles; inhibitors; kinases; structure-activity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Benzothiazoles
  • Protein Kinase Inhibitors
  • aminobenzothiazole compound
  • rho-Associated Kinases