title: Discovery and optimization of benzenesulfonanilide derivatives as a novel class of 11β-HSD1 inhibitors.
abstract: A novel series of benzenesulfonanilide derivatives of 11β-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11β-HSD1 SPA IC(50)=1.8 and 1.4 nM, respectively).
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. yrew@amgen.com
authors.forename: Yosup
authors.initials: Y
authors.lastname: Rew
authors.forename: Michael
authors.initials: M
authors.lastname: DeGraffenreid
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.forename: Juan C
authors.initials: JC
authors.lastname: Jaen
authors.forename: Dustin L
authors.initials: DL
authors.lastname: McMinn
authors.forename: Daqing
authors.initials: D
authors.lastname: Sun
authors.forename: Hua
authors.initials: H
authors.lastname: Tu
authors.forename: Stefania
authors.initials: S
authors.lastname: Ursu
authors.forename: Jay P
authors.initials: JP
authors.lastname: Powers
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008968:Molecular Conformation; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014162:Transfection
chemical_list: D000813:Anilides; D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D010879:Piperazines; D013449:Sulfonamides; D000077489:Piperazine; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1