Discovery and optimization of benzenesulfonanilide derivatives as a novel class of 11β-HSD1 inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 11; pp. 3786 - 3790
• Main Authors: Rew, Yosup, DeGraffenreid, Michael, He, Xiao, Jaen, Juan C., McMinn, Dustin L., Sun, Daqing, Tu, Hua, Ursu, Stefania, Powers, Jay P.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.06.2012; Elsevier
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - pharmacology; 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor; alcohol oxidoreductases; Anilides - chemical synthesis; Anilides - chemistry; Aniline Compounds - chemical synthesis; Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Benzenesulfonanilide; Biological and medical sciences; Crystallography, X-Ray; Drug Evaluation, Preclinical; Enzyme Activation - drug effects; enzyme inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HEK293 Cells; Humans; in vitro studies; Medical sciences; Molecular Conformation; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Structure-Activity Relationship; structure-activity relationships; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; system optimization; Transfection; 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor; Benzenesulfonanilide; 11β-Hydroxysteroid dehydrogenase type 1; Enzyme; Isozyme; 11β-Hydroxysteroid dehydrogenase; Enzyme inhibitor; Oxidoreductases; Optimization; (11β-HSD1) inhibitor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.04.005

The discovery and optimization of a benzenesulfonanilide series of 11β-HSD1 inhibitors is reported. 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 IC50=1.8 and 1.4nM, respectively).