Further studies with the 2-amino-1,3-thiazol-4(5H)-one class of 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: reducing pregnane X receptor activity and exploring activity in a monkey pharmacodynamic model.

Article Details

Citation

Fotsch C, Bartberger MD, Bercot EA, Chen M, Cupples R, Emery M, Fretland J, Guram A, Hale C, Han N, Hickman D, Hungate RW, Hayashi M, Komorowski R, Liu Q, Matsumoto G, St Jean DJ Jr, Ursu S, Veniant M, Xu G, Ye Q, Yuan C, Zhang J, Zhang X, Tu H, Wang M

Further studies with the 2-amino-1,3-thiazol-4(5H)-one class of 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: reducing pregnane X receptor activity and exploring activity in a monkey pharmacodynamic model.

J Med Chem. 2008 Dec 25;51(24):7953-67. doi: 10.1021/jm801073z.

PubMed ID
19053753 [ View in PubMed
]
Abstract

A series of compounds containing the 2-amino-1,3-thiazol-4(5H)-one core were found to be potent inhibitors of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). One of our lead compounds from this series activated the human nuclear xenobiotic receptor, pregnane X receptor (PXR). To try and mitigate the PXR activity, we prepared analogues of our lead series that contained polar groups on the right-hand side of the thiazolone. Several analogues containing amides or alcohols appended to the C-5 position of the thiazolone showed a significant reduction in PXR activity. Through these structure-activity efforts, a compound containing a tert-alcohol group off the C-5 position, analogue (S)-33a, was found to have an 11beta-HSD1 Ki = 35 nM and negligible PXR activity. Compound (S)-33a was advanced into a pharmacodynamic model in cynomolgus monkeys, where it inhibited adipose 11beta-HSD1 activity after being orally administered.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
(5S)-2-{[(1S)-1-(2-fluorophenyl)ethyl]amino}-5-methyl-5-(trifluoromethyl)-1,3-thiazol-4(5H)-oneCorticosteroid 11-beta-dehydrogenase isozyme 1Ki (nM)22N/AN/ADetails
(5S)-2-{[(1S)-1-(4-Fluorophenyl)ethyl]amino}-5-(2-hydroxy-2-propanyl)-5-methyl-1,3-thiazol-4(5H)-oneCorticosteroid 11-beta-dehydrogenase isozyme 1Ki (nM)35N/AN/ADetails
(5S)-2-{[(1S)-1-(4-Fluorophenyl)ethyl]amino}-5-(2-hydroxy-2-propanyl)-5-methyl-1,3-thiazol-4(5H)-oneCorticosteroid 11-beta-dehydrogenase isozyme 1IC 50 (nM)34N/AN/ADetails