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ID: ALA1821579
Journal: Bioorg Med Chem Lett
Title: Discovery of amide replacements that improve activity and metabolic stability of a bis-amide smoothened antagonist hit.
Authors: Brown ML, Aaron W, Austin RJ, Chong A, Huang T, Jiang B, Kaizerman JA, Lee G, Lucas BS, McMinn DL, Orf J, Rong M, Toteva MM, Xu G, Ye Q, Zhong W, Degraffenreid MR, Wickramasinghe D, Powers JP, Hungate R, Johnson MG.
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.
CiteXplore: 21840217