2. Academic Validation
  3. Optimization of cyclic sulfamide derivatives as 11β-hydroxysteroid dehydrogenase 1 inhibitors for the potential treatment of ischemic brain injury

Optimization of cyclic sulfamide derivatives as 11β-hydroxysteroid dehydrogenase 1 inhibitors for the potential treatment of ischemic brain injury

  • Bioorg Med Chem Lett. 2020 Jan 15;30(2):126787. doi: 10.1016/j.bmcl.2019.126787.
Jeong Hyun Lee 1,  Ju Hwan Bok 1,  Sung Bum Park 1,  Haushabhau S Pagire 2,  Yoon-Ju Na 3,  Eunyoung Rim 4,  Won Hoon Jung 1,  Jin Sook Song 1,  Nam Sook Kang 5,  Ho Won Seo 1,  Kwan-Young Jung 6,  Byung Ho Lee 3,  Ki Young Kim 7,  Jin Hee Ahn 8
Affiliations

Affiliations

  • 1 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
  • 2 Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
  • 3 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34183, Republic of Korea.
  • 4 Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Republic of Korea.
  • 5 Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34183, Republic of Korea.
  • 6 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Republic of Korea.
  • 7 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34183, Republic of Korea. Electronic address: kykim@krict.re.kr.
  • 8 Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea. Electronic address: jhahn@gist.ac.kr.
PMID: 31759849 DOI: 10.1016/j.bmcl.2019.126787
Abstract

The 11β-hydroxysteroiddehydrogenase type 1(11β-HSD1), acortisolregenerating enzyme that amplifies tissue glucocorticoidlevels, plays an important role in diabetes, obesity, and glaucoma and is recognized as a potential therapeutic target for various disease conditions. Moreover, a recent study demonstrated that selective 11β-HSD1 inhibitor can attenuate ischemic brain injury. This prompted us to optimize cyclic sulfamide derivative for aiming to treat ischemic brain injury. Among the synthesized compounds, 6e has an excellent in vitro activivity with an IC50 value of 1 nM toward human and mouse 11β-HSD1 and showed good 11β-HSD1 inhibition in ex vivo study using brain tissue isolated from mice. Furthermore, in the transient middle cerebral artery occlusion model in mice, 6e treatment significantly attenuated infarct volume and neurological deficit following cerebral ischemia/reperfusion injury. Additionally, binding modes of 6e for human and mouse 11β-HSD1 were suggested.

Keywords

11β-Hydroxysteroid dehydrogenase type 1; Cerebral ischemia; Inhibitors; Middle cerebral artery occlusion; Neuroprotection.

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