title: Discovery of amide replacements that improve activity and metabolic stability of a bis-amide smoothened antagonist hit.
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.
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Brown
authors.forename: Wade
authors.initials: W
authors.lastname: Aaron
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Austin
authors.forename: Angela
authors.initials: A
authors.lastname: Chong
authors.forename: Tom
authors.initials: T
authors.lastname: Huang
authors.forename: Ben
authors.initials: B
authors.lastname: Jiang
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Kaizerman
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.forename: Brian S
authors.initials: BS
authors.lastname: Lucas
authors.forename: Dustin L
authors.initials: DL
authors.lastname: McMinn
authors.forename: Jessica
authors.initials: J
authors.lastname: Orf
authors.forename: Minqing
authors.initials: M
authors.lastname: Rong
authors.forename: Maria M
authors.initials: MM
authors.lastname: Toteva
authors.forename: Guifen
authors.initials: G
authors.lastname: Xu
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Ye
authors.forename: Wendy
authors.initials: W
authors.lastname: Zhong
authors.forename: Michael R
authors.initials: MR
authors.lastname: Degraffenreid
authors.forename: Dineli
authors.initials: D
authors.lastname: Wickramasinghe
authors.forename: Jay P
authors.initials: JP
authors.lastname: Powers
authors.forename: Randall
authors.initials: R
authors.lastname: Hungate
authors.forename: Michael G
authors.initials: MG
authors.lastname: Johnson
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000577:Amides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D000217:Acyltransferases