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

被引：61

作者：

Li, Hong-Yu ^{[1
]}

McMillen, William T. ^{[1
]}

Heap, Charles R. ^{[6
]}

McCann, Denis J. ^{[2
]}

Yan, Lei ^{[3
]}

Campbell, Robert M. ^{[4
]}

Mundla, Sreenivasa R. ^{[5
]}

King, Chi-Hsin R. ^{[6
]}

Dierks, Elizabeth A. ^{[2
]}

Anderson, Bryan D. ^{[4
]}

Britt, Karen S. ^{[4
]}

Huss, Karen L. ^{[4
]}

Voss, Matthew D. ^{[5
]}

Wang, Yan ^{[1
]}

Clawson, David K. ^{[1
]}

Yingling, Jonathan M. ^{[3
]}

Sawyer, J. Scott ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Discovery Chem Res & Technol, Indianapolis, IN 46285 USA

[2] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Drug Disposit Res, Indianapolis, IN 46285 USA

[3] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Canc Res, Indianapolis, IN 46285 USA

[4] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Lead Optimizat Biol, Indianapolis, IN 46285 USA

[5] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Chem Prod Res & Dev, Indianapolis, IN 46285 USA

[6] Albany Mol Res Inc, Dept Med Chem, Albany, NY 12212 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 07期

关键词：

D O I：

10.1021/jm701199p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：2302 / 2306

页数：5

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