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

Publication date: Available online 29 April 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Linghang Zhuang, Colin M. Tice, Zhenrong Xu, Wei Zhao, Salvacion Cacatian, Yuan-Jie Ye, Suresh B. Singh, Peter Lindblom, Brian M. McKeever, Paula M. Krosky, Yi Zhao, Deepak Lala, Barbara A. Kruk, Shi Meng, Lamont Howard, Judith A. Johnson, Yuri Bukhtiyarov, Reshma Panemangalore, Joan Guo, Rong Guo, Frank Himmelsbach, Bradford Hamilton, Annette Schuler-Metz, Heike Schauerte, Richard Gregg, Gerard M. McGeehan, Katerina Leftheris, David A. Claremon
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 4.3 nM and in primary human adipose tissue with an IC80 of 53 nM. Oral administration of 11j to cynomolgus monkey inhibited 11β HSD1 activity in adipose tissue. Compound 11j exhibited > 1000x selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011.

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