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

Russell A Judge; Anil Vasudevan; Victoria E Scott; Gricelda H Simler; Steve D Pratt; Marian T Namovic; C Brent Putman; Ana Aguirre; Vincent S Stoll; Mulugeta Mamo; Steven I Swann; Steven C Cassar; Connie R Faltynek; Karen L Kage; Janel M Boyce-Rustay; Adrian D Hobson

doi:10.1002/cbic.201700547

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.

Authors

Russell A Judge¹, Anil Vasudevan¹, Victoria E Scott¹, Gricelda H Simler², Steve D Pratt¹, Marian T Namovic¹, C Brent Putman¹, Ana Aguirre¹, Vincent S Stoll¹, Mulugeta Mamo^{1

3}, Steven I Swann^{1

4}, Steven C Cassar¹, Connie R Faltynek¹, Karen L Kage^{1

5}, Janel M Boyce-Rustay^{1

6}, Adrian D Hobson²

Affiliations

¹ AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
² AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA.
³ Current address: Novartis Institute for Biomedical Research, 4560 Horton Street, Emeryville, CA, 94608, USA.
⁴ Current address: Takeda Pharmaceuticals, 10410 Science Center Drive, San Diego, CA, 92121, USA.
⁵ Current address: Altor Bioscience, 2810 North Commerce Parkway, Miramar, FL, 33025, USA.
⁶ Current address: Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.

PMID: 29314498
DOI: 10.1002/cbic.201700547

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