The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors.

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Yuan C, St Jean DJ Jr, Liu Q, Cai L, Li A, Han N, Moniz G, Askew B, Hungate RW, Johansson L, Tedenborg L, Pyring D, Williams M, Hale C, Chen M, Cupples R, Zhang J, Jordan S, Bartberger MD, Sun Y, Emery M, Wang M, Fotsch C

The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors.

Bioorg Med Chem Lett. 2007 Nov 15;17(22):6056-61. Epub 2007 Sep 25.

PubMed ID

17919905 [ View in PubMed

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Abstract

A series of 2-anilinothiazolones were prepared as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-position of the thiazolone ring (compounds 2 and 3, respectively). The binding mode was determined through the X-ray co-crystal structure of the enzyme with compound 3. This compound was also approximately 70-fold selective over 11beta-HSD2 and was orally bioavailable in rat pharmacokinetic studies. However, compound 3 was >580-fold less active in the 11beta-HSD1 cell assay when tested in the presence of 3% human serum albumin.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Corticosteroid 11-beta-dehydrogenase isozyme 1	P28845	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(5R)-2-[(2-Fluorophenyl)amino]-5-isopropyl-1,3-thiazol-4(5H)-one	Corticosteroid 11-beta-dehydrogenase isozyme 1	Ki (nM)	7	N/A	N/A	Details
(5R)-2-[(2-Fluorophenyl)amino]-5-isopropyl-1,3-thiazol-4(5H)-one	Corticosteroid 11-beta-dehydrogenase isozyme 1	IC 50 (nM)	15	N/A	N/A	Details