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

ACS Med Chem Lett. 2011 Dec 21;3(2):106-11. doi: 10.1021/ml2002423. eCollection 2012 Feb 9.


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.

Keywords: Hedgehog signaling pathway; PF-04449913; Smoothened.