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J Med Chem. 2015 May 28;58(10):4309-24. doi: 10.1021/acs.jmedchem.5b00308. Epub 2015 May 6.

Design, synthesis, and biological evaluation of novel, highly active soft ROCK inhibitors.

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†Amakem Therapeutics, Agoralaan Abis, 3590 Diepenbeek, Belgium.
‡CSD Farmakem, Elvire Boelensstraat 7, 9160 Lokeren, Belgium.


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.

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