8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors

Robert L. Hudkins, Allison L. Zulli, Ted L. Underiner, Thelma S. Angeles, Lisa D. Aimone, Sheryl L. Meyer, Daniel Pauletti, Hong Chang, Elena V. Fedorov, Steven C. Almo, Alexander A. Fedorov, Bruce A. Ruggeri

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


A novel series of 8-(2-tetrahydropyranyl)-12,13-dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazoles (THP-DHI) was synthesized and evaluated as dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors. Development of the structure-activity relationships (SAR) with the support of X-ray crystallography led to identification of 7f and 7g as potent, selective dual TIE-2/VEGF-R2 inhibitors with excellent cellular potency and acceptable pharmacokinetic properties. Compounds 7f and 7g were orally active in tumor models with no observed toxicity.

Original languageEnglish (US)
Pages (from-to)3356-3360
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number11
StatePublished - Jun 1 2010


  • Angiogenesis
  • Kinase inhibitor
  • TIE-2
  • VEGF-R2

ASJC Scopus subject areas

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


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