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ACS Med Chem Lett. 2011 Dec 21;3(2):106-11. doi: 10.1021/ml2002423. eCollection 2012.

Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened.

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  • 1Michael J. Munchhof LLC , 266 West Road, Salem, Connecticut 06420, United States.
  • 2Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
  • 324 Queen Eleanor Drive, Gales Ferry, Connecticut 06335, United States.
  • 4INC Research , Old Lyme, Connecticut 06371, United States.
  • 5Reiter.MedChem , 32 West Mystic Avenue, Mystic, Connecticut 06355, United States.
  • 6Bristol-Meyers Squibb , Princeton, New Jersey 08540, United States.


Inhibitors of the Hedgehog signaling pathway have generated a great deal of interest in the oncology area due to the mounting evidence of their potential to provide promising therapeutic options for patients. Herein, we describe the discovery strategy to overcome the issues inherent in lead structure 1 that resulted in the identification of Smoothened inhibitor 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea (PF-04449913, 26), which has been advanced to human clinical studies.


Hedgehog signaling pathway; PF-04449913; Smoothened

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