3G49

N-(Pyridin-2-yl) Arylsulfonamide Inhibitors of 11b-Hydroxysteroid Dehydrogenase Type 1: Discovery of PF-915275

Summary for 3G49

• Entry DOI: 10.2210/pdb3g49/pdb
• Descriptor: 11-beta-hydroxysteroid dehydrogenase 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-(6-{[(3-chloro-2-methylphenyl)sulfonyl]amino}pyridin-2-yl)-N,N-diethylacetamide, ... (4 entities in total)
• Functional Keywords: 11beta-hydroxysteroid dehydrogenase, inhibited, endoplasmic reticulum, glycoprotein, lipid metabolism, membrane, nadp, oxidoreductase, signal-anchor, steroid metabolism, transmembrane, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Cavia porcellus (guinea pig)
• Total number of polymer chains: 4
• Total formula weight: 125566.74

Authors

Pauly, T.A. (deposition date: 2009-02-03, release date: 2009-08-04, Last modification date: 2024-02-21)

Primary citation

Siu, M.,Johnson, T.O.,Wang, Y.,Nair, S.K.,Taylor, W.D.,Cripps, S.J.,Matthews, J.J.,Edwards, M.P.,Pauly, T.A.,Ermolieff, J.,Castro, A.,Hosea, N.A.,LaPaglia, A.,Fanjul, A.N.,Vogel, J.E.
N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275.
Bioorg.Med.Chem.Lett., 19:3493-3497, 2009

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.

PubMed: 19473839
DOI: 10.1016/j.bmcl.2009.05.011

Experimental method

X-RAY DIFFRACTION (2.5 Å)