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 journalArticle

11 Citations (Scopus)

Abstract

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
Volume20
Issue number11
DOIs
StatePublished - Jun 1 2010

Fingerprint

Carbazoles
Vascular Endothelial Growth Factor Receptor
X Ray Crystallography
Receptor Protein-Tyrosine Kinases
Structure-Activity Relationship
Protein-Tyrosine Kinases
Vascular Endothelial Growth Factor A
Pharmacokinetics
X ray crystallography
Toxicity
Tumors
Neoplasms

Keywords

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

ASJC Scopus subject areas

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

Cite this

Hudkins, R. L., Zulli, A. L., Underiner, T. L., Angeles, T. S., Aimone, L. D., Meyer, S. L., ... Ruggeri, B. A. (2010). 8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors. Bioorganic and Medicinal Chemistry Letters, 20(11), 3356-3360. https://doi.org/10.1016/j.bmcl.2010.04.021

8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors. / Hudkins, Robert L.; Zulli, Allison L.; Underiner, Ted L.; Angeles, Thelma S.; Aimone, Lisa D.; Meyer, Sheryl L.; Pauletti, Daniel; Chang, Hong; Fedorov, Elena V.; Almo, Steven C.; Fedorov, Alexander A.; Ruggeri, Bruce A.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 20, No. 11, 01.06.2010, p. 3356-3360.

Research output: Contribution to journalArticle

Hudkins, RL, Zulli, AL, Underiner, TL, Angeles, TS, Aimone, LD, Meyer, SL, Pauletti, D, Chang, H, Fedorov, EV, Almo, SC, Fedorov, AA & Ruggeri, BA 2010, '8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 11, pp. 3356-3360. https://doi.org/10.1016/j.bmcl.2010.04.021
Hudkins, Robert L. ; Zulli, Allison L. ; Underiner, Ted L. ; Angeles, Thelma S. ; Aimone, Lisa D. ; Meyer, Sheryl L. ; Pauletti, Daniel ; Chang, Hong ; Fedorov, Elena V. ; Almo, Steven C. ; Fedorov, Alexander A. ; Ruggeri, Bruce A. / 8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2010 ; Vol. 20, No. 11. pp. 3356-3360.
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