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Bioorg Med Chem Lett. 2011 Sep 15;21(18):5206-9. doi: 10.1016/j.bmcl.2011.07.052. Epub 2011 Jul 23.

Discovery of amide replacements that improve activity and metabolic stability of a bis-amide smoothened antagonist hit.

Author information

1
Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.

Abstract

A bis-amide antagonist of Smoothened, a seven-transmembrane receptor in the Hedgehog signaling pathway, was discovered via high throughput screening. In vitro and in vivo experiments demonstrated that the bis-amide was susceptible to N-acyl transferase mediated amide scission. Several bioisosteric replacements of the labile amide that maintained in vitro potency were identified and shown to be metabolically stable in vitro and in vivo.

PMID:
21840217
DOI:
10.1016/j.bmcl.2011.07.052
[Indexed for MEDLINE]

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