Discovery of novel, potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) exhibiting oral activity in an enzyme inhibition ex vivo model.

Article Details

Citation

Julian LD, Wang Z, Bostick T, Caille S, Choi R, DeGraffenreid M, Di Y, He X, Hungate RW, Jaen JC, Liu J, Monshouwer M, McMinn D, Rew Y, Sudom A, Sun D, Tu H, Ursu S, Walker N, Yan X, Ye Q, Powers JP

Discovery of novel, potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) exhibiting oral activity in an enzyme inhibition ex vivo model.

J Med Chem. 2008 Jul 10;51(13):3953-60. doi: 10.1021/jm800310g. Epub 2008 Jun 14.

PubMed ID
18553955 [ View in PubMed
]
Abstract

We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Corticosteroid 11-beta-dehydrogenase isozyme 1P28845Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
N-cyclopropyl-N-(trans-4-pyridin-3-ylcyclohexyl)-4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]benzamideCorticosteroid 11-beta-dehydrogenase isozyme 1IC 50 (nM)124N/AN/ADetails
N-cyclopropyl-N-(trans-4-pyridin-3-ylcyclohexyl)-4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]benzamideCorticosteroid 11-beta-dehydrogenase isozyme 1IC 50 (nM)3N/AN/ADetails
N-cyclopropyl-N-(trans-4-pyridin-3-ylcyclohexyl)-4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]benzamideCorticosteroid 11-beta-dehydrogenase isozyme 1IC 50 (nM)1.4N/AN/ADetails
N-cyclopropyl-N-(trans-4-pyridin-3-ylcyclohexyl)-4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]benzamideCorticosteroid 11-beta-dehydrogenase isozyme 1IC 50 (nM)5.8N/AN/ADetails