Pan, Jinpeng; Yin, Yan; Zhao, Lianhua; Feng, Yangbo published the artcile< Discovery of (S)-6-methoxy-chroman-3-carboxylic acid (4-pyridin-4-yl-phenyl)-amide as potent and isoform selective ROCK2 inhibitors>, Synthetic Route of 936250-20-3, the main research area is ROCK2 inhibitor selectivity methoxychromancarboxylatepyridin phenylamide; Chromans; Computational theoretical studies; Isoform selectivity; ROCK; ROCK inhibitors.
ROCK1 and ROCK2 are highly homologous isoforms. Accumulated studies indicate that they have distinct different functions, and the development of isoform selective ROCK inhibitors will pave new roads for the treatment of various diseases. In this work, a series of amide-chroman derivatives were synthesized and biol. evaluated in order to develop potent and isoform selective ROCK2 inhibitors. Remarkably, (S)-6-methoxy-chroman-3-carboxylic acid (4-pyridin-4-yl-phenyl)-amide ((S)-7c) possessed ROCK2 inhibitory activity with an IC50 value of 3 nM and 22.7-fold isoform selectivity (vs. ROCK1). Mol. docking indicated that hydrophobic interactions were the key element for the high potency and isoform selectivity of (S)-7c. The binding free energies predicted by MM/GBSA were in good agreement with the exptl. bioactivities, and the anal. of individual energy terms suggested that residue Lys105 in ROCK1 or Lys121 in ROCK2 was the key residue for the isoform selectivity of (S)-7c.
Bioorganic & Medicinal Chemistry published new progress about Free energy of binding. 936250-20-3 belongs to class pyrazoles-derivatives, and the molecular formula is C10H17BN2O2, Synthetic Route of 936250-20-3.
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