Tetrahydroisoquinoline derivatives as highly selective and potent rho kinase inhibitors

Xingang Fang, Yan Yin, Yen Ting Chen, Lei Yao, Bo Wang, Michael D. Cameron, Li Lin, Susan Khan, Claudia Ruiz, Thomas Schröter, Wayne Grant, Amiee Weiser, Jennifer Pocas, Alok Pachori, Stephans Schürer, Philip Lograsso, Yangbo Feng

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Rho kinase (ROCK) is a promising drug target for the treatment of many diseases including hypertension, multiple sclerosis, cancer, and glaucoma. The structure-activity relationships (SAR) around a series of tetrahydroisoquinolines were evaluated utilizing biochemical and cell-based assays to measure ROCK inhibition. These novel ROCK inhibitors possess high potency, high selectivity, and appropriate pharmacokinetic properties for glaucoma applications. The lead compound, 35, had subnanomolar potency in enzyme ROCK-II assays as well as excellent cell-based potency (IC50 = 51 nM). In a kinase panel profiling, 35 had an off-target hit rate of only 1.6% against 442 kinases. Pharmacology studies showed that compound 35 was efficacious in reducing intraocular pressure (IOP) in rats with reasonably long duration of action. These results suggest that compound 35 may serve as a promising agent for further development in the treatment of glaucoma.

Original languageEnglish (US)
Pages (from-to)5727-5737
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number15
DOIs
StatePublished - Aug 12 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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