The discovery of 2-anilinothiazolones as 11β-HSD1 inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 22; pp. 6056 - 6061
• Main Authors: Yuan, Chester, St. Jean, David J., Liu, Qingyian, Cai, Lynn, Li, Aiwen, Han, Nianhe, Moniz, George, Askew, Ben, Hungate, Randall W., Johansson, Lars, Tedenborg, Lars, Pyring, David, Williams, Meredith, Hale, Clarence, Chen, Michelle, Cupples, Rod, Zhang, Jiandong, Jordan, Steven, Bartberger, Michael D., Sun, Yaxiong, Emery, Maurice, Wang, Minghan, Fotsch, Christopher
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.11.2007; Elsevier
• Subjects: 11β-HSD1; 11β-Hydroxysteroid dehydrogenase type 1; Biological and medical sciences; Medical sciences; Metabolic syndrome; Miscellaneous; Pharmacology. Drug treatments; Thiazolone; 11β-Hydroxysteroid dehydrogenase type 1; 11β-HSD1; Metabolic syndrome; Thiazolone; Endocrinopathy; Rat; Isozyme; Thiazole derivatives; Active site; Cardiovascular disease; Molecular interaction; Selectivity; Structure activity relation; 11β-Hydroxysteroid dehydrogenase; Chemical synthesis; Enzyme; Rodentia; Enzyme inhibitor; Metabolic diseases; Aniline derivatives; In vitro; In vivo; Vertebrata; Mammalia; Animal; Oxidoreductases; Pharmacokinetics; Aromatic amine
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2007.09.070

A series of 2-anilinothiazolones were prepared as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-position of the thiazolone ring (compounds 2 and 3, respectively). The binding mode was determined through the X-ray co-crystal structure of the enzyme with compound 3. This compound was also ∼70-fold selective over 11β-HSD2 and was orally bioavailable in rat pharmacokinetic studies. However, compound 3 was >580-fold less active in the 11β-HSD1 cell assay when tested in the presence of 3% human serum albumin.