Discovery and optimization of piperidyl benzamide derivatives as a novel class of 11beta-HSD1 inhibitors.

Article Details

Citation

Rew Y, McMinn DL, Wang Z, He X, Hungate RW, Jaen JC, Sudom A, Sun D, Tu H, Ursu S, Villemure E, Walker NP, Yan X, Ye Q, Powers JP

Discovery and optimization of piperidyl benzamide derivatives as a novel class of 11beta-HSD1 inhibitors.

Bioorg Med Chem Lett. 2009 Mar 15;19(6):1797-801. doi: 10.1016/j.bmcl.2009.01.058. Epub 2009 Jan 23.

PubMed ID
19217779 [ View in PubMed
]
Abstract

Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Corticosteroid 11-beta-dehydrogenase isozyme 1P28845Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
N-{1-[(1-carbamoylcyclopropyl)methyl]piperidin-4-yl}-N-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]benzamideCorticosteroid 11-beta-dehydrogenase isozyme 1IC 50 (nM)147.522Details
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)1.47.522Details