N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275.

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Siu M, Johnson TO, Wang Y, Nair SK, Taylor WD, Cripps SJ, Matthews JJ, Edwards MP, Pauly TA, Ermolieff J, Castro A, Hosea NA, LaPaglia A, Fanjul AN, Vogel JE

N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275.

Bioorg Med Chem Lett. 2009 Jul 1;19(13):3493-7. doi: 10.1016/j.bmcl.2009.05.011. Epub 2009 May 7.

PubMed ID

19473839 [ View in PubMed

]

Abstract

N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
2-(6-{[(3-chloro-2-methylphenyl)sulfonyl]amino}pyridin-2-yl)-N,N-diethylacetamide	Corticosteroid 11-beta-dehydrogenase isozyme 1	Ki (nM)	287	8	22	Details