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

  • J Med Chem. 2008 Apr 10;51(7):2302-6. doi: 10.1021/jm701199p.
Hong-Yu Li  1 ,  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
Affiliations
  • 1. Discovery Chemistry Research and Technology, Lead Optimization Biology, and Chemical Product Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. [email protected]
PMID: 18314943 DOI: 10.1021/jm701199p
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.

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