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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.

SUBMITTER: Munchhof MJ

PROVIDER: S-EPMC4025788 | biostudies-other | 2012 Feb

REPOSITORIES: biostudies-other

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

Munchhof Michael J MJ Li Qifang Q Shavnya Andrei A Borzillo Gary V GV Boyden Tracey L TL Jones Christopher S CS LaGreca Susan D SD Martinez-Alsina Luis L Patel Nandini N Pelletier Kathleen K Reiter Larry A LA Robbins Michael D MD Tkalcevic George T GT

ACS medicinal chemistry letters 20111221 2

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 huma ...[more]

PMID: 24900436

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