Identification of 5H-chromeno[3,4-c]pyridine and 6H-isochromeno[3,4-c]pyridine derivatives as potent and selective dual ROCK inhibitors |
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| Institution: | 1. U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy;2. Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy;1. Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan;2. Takeda California, Inc., 10410 Science Center Drive, San Diego 92121, CA, USA;1. Laboratory of Growth Regulators, The Czech Academy of Sciences, Institute of Experimental Botany & Palacký University, ?lechtitel? 27, CZ-78371 Olomouc, Czech Republic;2. Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15 Olomouc, Czech Republic;3. Isotope Laboratory, The Czech Academy of Sciences, Institute of Experimental Botany, Vídeňská 1083, 142 00 Prague 4, Czech Republic;4. Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University, ?lechtitel? 27, CZ-78371 Olomouc, Czech Republic;5. Department of Cell Biology, Faculty of Science, Charles University in Prague, Vini?ná 7, 12843, Prague 2, Czech Republic |
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| Abstract: | A novel series of 5H-chromeno3,4-c]pyridine, 6H-isochromeno3,4-c]pyridine and 6H-isochromeno4,3-d]pyrimidine derivatives as dual ROCK1 and ROCK2 inhibitors is described. Optimization led to compounds with sub-nanomolar inhibitory affinity for both kinases and excellent kinome selectivity. Compound 19 exhibited ROCK1 and ROCK2 IC50 of 0.67 nM and 0.18 nM respectively. |
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| Keywords: | Rho kinase ROCK inhibitor Chromenopyridine Chromenopyrimidine |
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