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Bioorg Med Chem Lett. 2015 Sep 1;25(17):3501-6. doi: 10.1016/j.bmcl.2015.06.099. Epub 2015 Jul 4.

Discovery of 11β-hydroxysteroid dehydrogenase type 1 inhibitor.

Author information

1
Institute for New Drug Development, Division of Life Sciences, Incheon National University, Incheon 406-772, Republic of Korea.
2
Center for Development and Commercialization of Anti Cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, 138-736, Republic of Korea.
3
R & D Center, Ahn Gook Pharm., Suwon 443-766, Republic of Korea.
4
Institute for New Drug Development, Division of Life Sciences, Incheon National University, Incheon 406-772, Republic of Korea. Electronic address: skahn@incheon.ac.kr.

Abstract

Various adamantane sulfonamides showed potent inhibitory activity against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In continuation of our efforts to discover a more potent, selective and metabolically stable 11β-HSD1 inhibitor in mice as well as in humans, we optimized the adamantane sulfonamide using structure-based molecular modeling. Compound 3, which has alkyl side chains on the linker, demonstrated a potent inhibitory activity against human and mouse 11β-HSD1 (IC50 of 0.6 nM and 26 nM, respectively) and good physicochemical properties as a new anti-diabetes drug candidate.

KEYWORDS:

11-β-Hydroxysteroid dehydrogenase (11β-HSD1) inhibitor; Adamantane sulfonamide; Antidiabetes; Optimization; Structure-based molecular modeling

PMID:
26187704
DOI:
10.1016/j.bmcl.2015.06.099
[Indexed for MEDLINE]

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