Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I) |
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| Authors: | Chowdhury Sarwat Sessions E Hampton Pocas Jennifer R Grant Wayne Schröter Thomas Lin Li Ruiz Claudia Cameron Michael D Schürer Stephan LoGrasso Philip Bannister Thomas D Feng Yangbo |
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| Institution: | Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA. |
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| Abstract: | Rho kinase (ROCK) inhibitors are potential therapeutic agents to treat disorders such as hypertension, multiple sclerosis, cancers, and glaucoma. Here, we disclose the synthesis, optimization, biological evaluation of potent indole and 7-azaindole based ROCK inhibitors that have high potency on ROCK (IC(50)=1 nM) with 740-fold selectivity over PKA (47). Moreover, 47 showed very good DMPK properties making it a good candidate for further development. Finally, docking studies with a homology model of ROCK-II were performed to rationalize the binding mode of these compounds and showed the compounds bound in both orientations to take advantage to H-bonds with Lys-121 of ROCK-II. |
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| Keywords: | Rho kinase ROCK inhibitor Indole Azaindole Protein kinase A Pyrazole |
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