Rho-associated coiled-coil forming protein kinase (ROCK), members of the serine/threonine kinase family, plays a key role in cellular phenomena such as contraction of smooth muscles, morphological changes, etc. Therefore, inhibition of ROCK has been expected to provide effective anti-glaucoma activity.Our investigations of structure-activity relationship for ROCK inhibitors started from Y-27632 and Y-39983, and resulted in the identification of novel trisubstituted olefin derivatives, 6-substituted isoquinoline derivatives and 5-substituted indazole derivatives. Especially, 4-cyclopropyl, 5-pyridino indazole derivatives were significantly soluble in water, and showed the potent inhibition at in vitro studies and the strong reduction of intraocular pressure in cynomolgus monkey.

Design and synthesis of novel indazole derivatives as Rho kinase inhibitors

247th National Meeting (2014)

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