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ACS Med Chem Lett. 2012 Sep 20;3(10):793-8. doi: 10.1021/ml300144n. eCollection 2012 Oct 11.

Discovery of 2-Alkyl-1-arylsulfonylprolinamides as 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors.

Author information

1
Central Research Institute, Shanghai Pharmaceutical Holding Co., Ltd. , Building 5, 898 Ha Lei Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
2
Central Research Institute, Shanghai Pharmaceutical Holding Co., Ltd. , Building 5, 898 Ha Lei Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
3
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.

Abstract

On the basis of scaffold hopping, a novel series of 2-alkyl-1-arylsulfonylprolinamides was discovered as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) inhibitors. A representative compound 4ek, obtained through SAR and structure optimization studies, demonstrates excellent in vitro potency against 11β-HSD-1 and dose-dependent in vivo inhibition of 11β-HSD-1 in a prednisone/prednisolone transformation biomarker study in mice.

KEYWORDS:

11β-hydroxysteroid dehydrogenase type 1; 2-alkylproline; enzyme inhibitor; metabolic syndrome; prolinamide; sulfonamide

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