title: Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened.
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.
authors.affiliation: Michael J. Munchhof LLC , 266 West Road, Salem, Connecticut 06420, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Munchhof
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Qifang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Andrei
authors.initials: A
authors.lastname: Shavnya
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Gary V
authors.initials: GV
authors.lastname: Borzillo
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Boyden
authors.affiliation: 24 Queen Eleanor Drive, Gales Ferry, Connecticut 06335, United States.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Jones
authors.affiliation: INC Research , Old Lyme, Connecticut 06371, United States.
authors.forename: Susan D
authors.initials: SD
authors.lastname: LaGreca
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Luis
authors.initials: L
authors.lastname: Martinez-Alsina
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Nandini
authors.initials: N
authors.lastname: Patel
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Pelletier
authors.affiliation: Reiter.MedChem , 32 West Mystic Avenue, Mystic, Connecticut 06355, United States.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Reiter
authors.affiliation: Bristol-Meyers Squibb , Princeton, New Jersey 08540, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Robbins
authors.affiliation: Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
authors.forename: George T
authors.initials: GT
authors.lastname: Tkalcevic
keywords: Hedgehog signaling pathway; PF-04449913; Smoothened