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

Autor: Munchhof MJ; Michael J. Munchhof LLC , 266 West Road, Salem, Connecticut 06420, United States., Li Q; Pfizer Global Research and Development , Groton, Connecticut 06340, United States., Shavnya A; Pfizer Global Research and Development , Groton, Connecticut 06340, United States., Borzillo GV; Pfizer Global Research and Development , Groton, Connecticut 06340, United States., Boyden TL; Pfizer Global Research and Development , Groton, Connecticut 06340, United States., Jones CS; 24 Queen Eleanor Drive, Gales Ferry, Connecticut 06335, United States., LaGreca SD; INC Research , Old Lyme, Connecticut 06371, United States., Martinez-Alsina L; Pfizer Global Research and Development , Groton, Connecticut 06340, United States., Patel N; Pfizer Global Research and Development , Groton, Connecticut 06340, United States., Pelletier K; Pfizer Global Research and Development , Groton, Connecticut 06340, United States., Reiter LA; Reiter.MedChem , 32 West Mystic Avenue, Mystic, Connecticut 06355, United States., Robbins MD; Bristol-Meyers Squibb , Princeton, New Jersey 08540, United States., Tkalcevic GT; Pfizer Global Research and Development , Groton, Connecticut 06340, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2011 Dec 21; Vol. 3 (2), pp. 106-11. Date of Electronic Publication: 2011 Dec 21 (Print Publication: 2012).
DOI: 10.1021/ml2002423
Abstrakt: 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.
Databáze: MEDLINE
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