2. Academic Validation
  3. Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened

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.
Michael J Munchhof 1,  Qifang Li 2,  Andrei Shavnya 2,  Gary V Borzillo 2,  Tracey L Boyden 2,  Christopher S Jones 3,  Susan D LaGreca 4,  Luis Martinez-Alsina 2,  Nandini Patel 2,  Kathleen Pelletier 2,  Larry A Reiter 5,  Michael D Robbins 6,  George T Tkalcevic 2
Affiliations

Affiliations

  • 1 Michael J. Munchhof LLC , 266 West Road, Salem, Connecticut 06420, United States.
  • 2 Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
  • 3 24 Queen Eleanor Drive, Gales Ferry, Connecticut 06335, United States.
  • 4 INC Research , Old Lyme, Connecticut 06371, United States.
  • 5 Reiter.MedChem , 32 West Mystic Avenue, Mystic, Connecticut 06355, United States.
  • 6 Bristol-Meyers Squibb , Princeton, New Jersey 08540, United States.
PMID: 24900436 DOI: 10.1021/ml2002423
Abstract

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.

Figures