The synthesis and SAR of novel diarylsulfone 11beta-HSD1 inhibitors.

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Yan X, Wang Z, Sudom A, Cardozo M, DeGraffenreid M, Di Y, Fan P, He X, Jaen JC, Labelle M, Liu J, Ma J, McMinn D, Miao S, Sun D, Tang L, Tu H, Ursu S, Walker N, Ye Q, Powers JP

The synthesis and SAR of novel diarylsulfone 11beta-HSD1 inhibitors.

Bioorg Med Chem Lett. 2010 Dec 1;20(23):7071-5. doi: 10.1016/j.bmcl.2010.09.097. Epub 2010 Sep 29.

PubMed ID

20971000 [ View in PubMed

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Abstract

In this communication, human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11beta-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
1-{[(3R)-3-methyl-4-({4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]phenyl}sulfonyl)piperazin-1-yl]methyl}cyclopropanecarboxamide	Corticosteroid 11-beta-dehydrogenase isozyme 1	IC 50 (nM)	0.83	N/A	N/A	Details
1-{[(3R)-3-methyl-4-({4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]phenyl}sulfonyl)piperazin-1-yl]methyl}cyclopropanecarboxamide	Corticosteroid 11-beta-dehydrogenase isozyme 1	IC 50 (nM)	7.3	N/A	N/A	Details