Optimization of a dihydropyrrolopyrazole series of transforming growth factor-β type I receptor kinase domain inhibitors: Discovery of an orally bioavailable transforming growth factor-β receptor type I inhibitor as antitumor agent

Hong Yu Li, William T. McMillen, Charles R. Heap, Denis J. McCann, Lei Yan, Robert M. Campbell, Sreenivasa R. Mundla, Chi Hsin R. King, Elizabeth A. Dierks, Bryan D. Anderson, Karen S. Britt, Karen L. Huss, Matthew D. Voss, Yan Wang, David K. Clawson, Jonathan M. Yingling, J. Scott Sawyer

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Abstract

In our continuing effort to expand the SAR of the quinoline domain of dihydropyrrolopyrazole series, we have discovered compound 15d, which demonstrated the antitumor efficacy with oral bioavailability. This effort also demonstrated that the PK/PD in vivo target inhibition paradigm is an effective approach to assess potential for antitumor efficacy. The dihydropyrrolopyrazole inhibitor 15d (LY2109761) is representative of a novel series of antitumor agents.

Original languageEnglish (US)
Pages (from-to)2302-2306
Number of pages5
JournalJournal of Medicinal Chemistry
Volume51
Issue number7
DOIs
StatePublished - Apr 10 2008

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Li, H. Y., McMillen, W. T., Heap, C. R., McCann, D. J., Yan, L., Campbell, R. M., Mundla, S. R., King, C. H. R., Dierks, E. A., Anderson, B. D., Britt, K. S., Huss, K. L., Voss, M. D., Wang, Y., Clawson, D. K., Yingling, J. M., & Sawyer, J. S. (2008). Optimization of a dihydropyrrolopyrazole series of transforming growth factor-β type I receptor kinase domain inhibitors: Discovery of an orally bioavailable transforming growth factor-β receptor type I inhibitor as antitumor agent. Journal of Medicinal Chemistry, 51(7), 2302-2306. https://doi.org/10.1021/jm701199p