2. Academic Validation
  3. Discovery of BI 135585, an in vivo efficacious oxazinanone-based 11β hydroxysteroid dehydrogenase type 1 inhibitor

Discovery of BI 135585, an in vivo efficacious oxazinanone-based 11β hydroxysteroid dehydrogenase type 1 inhibitor

  • Bioorg Med Chem. 2017 Jul 15;25(14):3649-3657. doi: 10.1016/j.bmc.2017.04.033.
Linghang Zhuang 1,  Colin M Tice 2,  Zhenrong Xu 2,  Wei Zhao 2,  Salvacion Cacatian 2,  Yuan-Jie Ye 2,  Suresh B Singh 2,  Peter Lindblom 2,  Brian M McKeever 3,  Paula M Krosky 3,  Yi Zhao 3,  Deepak Lala 3,  Barbara A Kruk 3,  Shi Meng 3,  Lamont Howard 3,  Judith A Johnson 3,  Yuri Bukhtiyarov 3,  Reshma Panemangalore 3,  Joan Guo 3,  Rong Guo 3,  Frank Himmelsbach 4,  Bradford Hamilton 4,  Annette Schuler-Metz 4,  Heike Schauerte 4,  Richard Gregg 3,  Gerard M McGeehan 3,  Katerina Leftheris 2,  David A Claremon 2
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Vitae Pharmaceuticals, Inc, 502 West Office Center Drive, Fort Washington, PA 19034, United States. Electronic address: [email protected].
  • 2 Medicinal Chemistry, Vitae Pharmaceuticals, Inc, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
  • 3 Biology, Vitae Pharmaceuticals, Inc, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
  • 4 Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach, Germany.
PMID: 28528082 DOI: 10.1016/j.bmc.2017.04.033
Abstract

A potent, in vivo efficacious 11β hydroxysteroid dehydrogenase type 1 (11β HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11β HSD1 activity in human adipocytes with an IC50 of 4.3nM and in primary human adipose tissue with an IC80 of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11β HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011.

Keywords

11beta hydroxysteroid dehydrogenase type 1; Human adipocyte; Human adipose tissue; Inhibitor; Oxazinanone.

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