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

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

doi:10.1016/j.bmc.2017.04.033

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. Epub 2017 Apr 29.

Authors

Linghang Zhuang¹, Colin M Tice², Zhenrong Xu², Wei Zhao², Salvacion Cacatian², Yuan-Jie Ye², Suresh B Singh², Peter Lindblom², Brian M McKeever³, Paula M Krosky³, Yi Zhao³, Deepak Lala³, Barbara A Kruk³, Shi Meng³, Lamont Howard³, Judith A Johnson³, Yuri Bukhtiyarov³, Reshma Panemangalore³, Joan Guo³, Rong Guo³, Frank Himmelsbach⁴, Bradford Hamilton⁴, Annette Schuler-Metz⁴, Heike Schauerte⁴, Richard Gregg³, Gerard M McGeehan³, Katerina Leftheris², David A Claremon²

Affiliations

¹ Medicinal Chemistry, Vitae Pharmaceuticals, Inc, 502 West Office Center Drive, Fort Washington, PA 19034, United States. Electronic address: linghang_zhuang@yahoo.com.
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.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
Adipose Tissue / cytology
Adipose Tissue / metabolism
Administration, Oral
Animals
Binding Sites
Cells, Cultured
Cytochrome P-450 Enzyme System / metabolism
Drug Evaluation, Preclinical
Half-Life
Inhibitory Concentration 50
Macaca fascicularis
Molecular Docking Simulation
Oxazines / administration & dosage
Oxazines / chemistry*
Oxazines / pharmacokinetics
Protein Structure, Tertiary
Pyridones / administration & dosage
Pyridones / chemistry*
Pyridones / pharmacokinetics
Rats
Structure-Activity Relationship

Substances

6-(2-hydroxy-2-methylpropyl)-3-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
Oxazines
Pyridones
Cytochrome P-450 Enzyme System
11-beta-Hydroxysteroid Dehydrogenase Type 1