Identification of Selective Dual ROCK1 and ROCK2 Inhibitors Using Structure-Based Drug Design

A HTS
campaign identified compound 1, an excellent
hit-like molecule to initiate medicinal chemistry efforts to optimize
a dual ROCK1 and ROCK2 inhibitor. Substitution (2-Cl, 2-NH2, 2-F, 3-F) of the pyridine hinge binding motif or replacement with
pyrimidine afforded compounds with a clean CYP inhibition profile.
Cocrystal structures of an early lead compound were obtained in PKA,
ROCK1, and ROCK2. This provided critical structural information for
medicinal chemistry to drive compound design. The structural data
indicated the preferred configuration at the central benzylic carbon
would be (R), and application of this information
to compound design resulted in compound 16. This compound
was shown to be a potent and selective dual ROCK inhibitor in both
enzyme and cell assays and efficacious in the retinal nerve fiber
layer model after oral dosing. This tool compound has been made available
through the AbbVie Compound Toolbox. Finally, the cocrystal structures
also identified that aspartic acid residues 176 and 218 in ROCK2,
which are glutamic acids in PKA, could be targeted as residues to
drive both potency and kinome selectivity. Introduction of a piperidin-3-ylmethanamine
group to the compound series resulted in compound 58,
a potent and selective dual ROCK inhibitor with excellent predicted
drug-like properties.