Design, Synthesis, and Biological Evaluation of Novel, Highly Active Soft ROCK Inhibitors

Abstract

ROCK1 and ROCK2 play important roles in numerous cellular functions, including smooth muscle cell contraction, cell proliferation, adhesion, and migration. Consequently, ROCK inhibitors are of interest for treating multiple indications including cardiovascular diseases, inflammatory and autoimmune diseases, lung diseases, and eye diseases. However, systemic inhibition of ROCK is expected to result in significant side effects. Strategies allowing reduced systemic exposure are therefore of interest. In a continuing effort toward identification of ROCK inhibitors, we here report the design, synthesis, and evaluation of novel soft ROCK inhibitors displaying an ester function allowing their rapid inactivation in the systemic circulation. Those compounds display subnanomolar activity against ROCK and strong differences of functional activity between parent compounds and expected metabolites. The binding mode of a representative compound was determined experimentally in a single-crystal X-ray diffraction study. Enzymes responsible for inactivation of these compounds once they enter systemic circulation are also discussed.

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

“…Newer ROCK inhibitors such as K-115 (Ripasudil), which have recently entered the clinic for the treatment of glaucoma (101,102) or are currently in the clinical testing pipeline, including phase 2 clinical trial for glaucoma (AMA0076) (103), or CCT129254 or AT13148, which reduce metastasis in other cancers (104), could also have similar applications (105). Patient presentation in PC ranges from early local invasion at the time of diagnosis to late metastatic disease (106).…”

Predicting the Enzymatic Hydrolysis Half‐lives of New Chemicals Using Support Vector Regression Models Based on Stepwise Feature Elimination

“…Thus, the number of carboxylate ester bonds (NCEB) is an important variable for stability. In addition, large differences in hydrolysis rates were indeed observed between compounds, and they were dependent on the nature of the ester group and its position, and sterically hindered esters are not always easy to hydrolyze . The variable of the CC(C)N fingerprint was likely selected because this branched carbon fingerprint has a steric effect on the ester bonds.…”

“…In either case, plasma enzymes can significantly alter the bioavailability of active compounds, which should be evaluated at early stages in the drug discovery process . Most in vitro plasma/blood stability assays for drugs contain ester bonds (greater than 85 % in our statics), and the half‐life (t1/2) value in human plasma/blood has been widely used to measure the stability level of pro‐drugs and soft‐drugs in previous studies …”

“…The hydrolysis of ester groups, which is the major metabolism pathway of chemicals in human plasma, is caused by the metabolism of various esterases, including butyrylcholinesterase (EC 3.1.1.8), paraoxonase (EC 3.1.8.1), acetylcholinesterase (EC 3.1.1.7), and albumin . Human plasma does not contain carboxylesterase (EC 3.1.1.1), whereas mouse, rat, rabbit, horse, cat, and tiger plasmas contain high amounts of plasma carboxylesterase .…”

Derivation of Self-inhibitory Helical Peptides to Target Rho-kinase Dimerization in Cerebrovascular Malformation: Structural Bioinformatics Analysis and Peptide Binding Assay

“…The formation of asymmetric dimer is a critical biological event for the Rho‐kinase activation. Crystallographic studies revealed that two Rho‐kinase monomers interact via a dimerization domain where two sets of helices, one set from each monomer, are twisted together to tightly pack against each other to stabilize the dimer . These helix motifs are connected by flexible loops and can work independently to interact with the partner monomer.…”