GDC-0449—A potent inhibitor of the hedgehog pathway
Graphical abstract
Starting from lead compound 1, rescaffolding gave 15. Further optimization resulted in the discovery of 2-pyridyl Hh antagonist 31 (GDC-0449), which is currently in human clinical trials.
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Acknowledgments
The authors thank Martin Struble and Mengling Wong for purification of compounds, Vickie Tsui for computational support, Harvey Wong for transport studies with GDC-0449, and Mike Reich and the in vivo group for their support of PK and PK/PD studies.
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