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Design of Aminobenzothiazole Inhibitors of Rho Kinases 1 and 2 by Using Protein Kinase A as a Structure Surrogate
Author(s) -
Judge Russell A.,
Vasudevan Anil,
Scott Victoria E.,
Simler Gricelda H.,
Pratt Steve D.,
Namovic Marian T.,
Putman C. Brent,
Aguirre Ana,
Stoll Vincent S.,
Mamo Mulugeta,
Swann Steven I.,
Cassar Steven C.,
Faltynek Connie R.,
Kage Karen L.,
BoyceRustay Janel M.,
Hobson Adrian D.
Publication year - 2018
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700547
Subject(s) - kinase , chemistry , phosphatase , in vivo , ex vivo , protein kinase a , rho associated protein kinase , biochemistry , enzyme , in vitro , biology , microbiology and biotechnology
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.