The discovery of new 11beta-hydroxysteroid dehydrogenase type 1 inhibitors by common feature pharmacophore modeling and virtual screening

Schuster, Daniela; Maurer, Evelyne M; Laggner, Christian; Nashev, Lyubomir G; Wilckens, Thomas; Langer, Thierry; Odermatt, Alex (2006). The discovery of new 11beta-hydroxysteroid dehydrogenase type 1 inhibitors by common feature pharmacophore modeling and virtual screening. Journal of medicinal chemistry, 49(12), pp. 3454-66. Easton, Pa.: American Chemical Society 10.1021/jm0600794

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11beta-Hydroxysteroid dehydrogenase (11beta-HSD) enzymes catalyze the conversion of biologically inactive 11-ketosteroids into their active 11beta-hydroxy derivatives and vice versa. Inhibition of 11beta-HSD1 has considerable therapeutic potential for glucocorticoid-associated diseases including obesity, diabetes, wound healing, and muscle atrophy. Because inhibition of related enzymes such as 11beta-HSD2 and 17beta-HSDs causes sodium retention and hypertension or interferes with sex steroid hormone metabolism, respectively, highly selective 11beta-HSD1 inhibitors are required for successful therapy. Here, we employed the software package Catalyst to develop ligand-based multifeature pharmacophore models for 11beta-HSD1 inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed several selective inhibitors. Efficient inhibition of recombinant human 11beta-HSD1 in intact transfected cells as well as endogenous enzyme in mouse 3T3-L1 adipocytes and C2C12 myotubes was demonstrated for compound 27, which was able to block subsequent cortisol-dependent activation of glucocorticoid receptors with only minor direct effects on the receptor itself. Our results suggest that inhibitor-based pharmacophore models for 11beta-HSD1 in combination with suitable cell-based activity assays, including such for related enzymes, can be used for the identification of selective and potent inhibitors.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
UniBE Contributor:	Odermatt, Alexander
ISSN:	0022-2623
ISBN:	16759088
Publisher:	American Chemical Society
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:50
Last Modified:	05 Dec 2022 14:15
Publisher DOI:	10.1021/jm0600794
PubMed ID:	16759088
Web of Science ID:	000238114700007
URI:	https://boris.unibe.ch/id/eprint/20902 (FactScience: 4698)