Synthesis and 11beta hydroxysteroid dehydrogenase 1 inhibition of thiazolidine derivatives with an adamantyl group.

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Kwon SW, Kang SK, Lee JH, Bok JH, Kim CH, Dal Rhee S, Jung WH, Kim HY, Bae MA, Song JS, Ha DC, Cheon HG, Kim KY, Ahn JH

Synthesis and 11beta hydroxysteroid dehydrogenase 1 inhibition of thiazolidine derivatives with an adamantyl group.

Bioorg Med Chem Lett. 2011 Jan 1;21(1):435-9. doi: 10.1016/j.bmcl.2010.10.123. Epub 2010 Nov 2.

PubMed ID

21093259 [ View in PubMed

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Abstract

A new series of thiazolidine derivatives with an adamantyl group was synthesized and evaluated for their ability to inhibit 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1). Our initial compound 5a showed a weak inhibitory activity. Significant improvements in potency were achieved by substituent modification. The potent compound 8g (E) showed good in vitro inhibitory activity toward human 11beta-HSD1, selectivity toward 11beta-HSD2, metabolic stability, pharmacokinetic, and safety profile. Furthermore, this compound significantly inhibited 11beta-HSD1 activity in rat and monkey models, and showed improved glycemic control in KKAy mice.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Carbenoxolone	Corticosteroid 11-beta-dehydrogenase isozyme 1	IC 50 (nM)	500	N/A	N/A	Details