Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I)

Sarwat Chowdhury, E. Hampton Sessions, Jennifer R. Pocas, Wayne Grant, Thomas Schröter, Li Lin, Claudia Ruiz, Michael D. Cameron, Stephan Schürer, Philip Lograsso, Thomas D. Bannister, Yangbo Feng

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7107-7112
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number23
DOIs
StatePublished - Dec 1 2011

Keywords

  • Azaindole
  • Indole
  • Protein kinase A
  • Pyrazole
  • Rho kinase
  • ROCK inhibitor

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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