4hx5

From Proteopedia

Crystal structure of 11 beta-HSD1 in complex with SAR184841

PDB ID 4hx5

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Structural highlights

4hx5 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.19Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DHI1_HUMAN Defects in HSD11B1 are a cause of cortisone reductase deficiency (CRD) [MIM:604931. In CRD, activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS).

Function

DHI1_HUMAN Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone. Catalyzes reversibly the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. In intact cells, the reaction runs only in one direction, from 7-ketocholesterol to 7-beta-hydroxycholesterol (By similarity).

Publication Abstract from PubMed

Starting from 11beta-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11beta-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.

Discovery of SAR184841, a potent and long-lasting inhibitor of 11beta-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D.,Venier O, Pascal C, Braun A, Namane C, Mougenot P, Crespin O, Pacquet F, Mougenot C, Monseau C, Onofri B, Dadji-Faihun R, Leger C, Ben-Hassine M, Van-Pham T, Ragot JL, Philippo C, Farjot G, Noah L, Maniani K, Boutarfa A, Nicolai E, Guillot E, Pruniaux MP, Gussregen S, Engel C, Coutant AL, de Miguel B, Castro A Bioorg Med Chem Lett. 2013 Apr 15;23(8):2414-21. doi: 10.1016/j.bmcl.2013.02.018., Epub 2013 Feb 22. PMID:23478147^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Venier O, Pascal C, Braun A, Namane C, Mougenot P, Crespin O, Pacquet F, Mougenot C, Monseau C, Onofri B, Dadji-Faihun R, Leger C, Ben-Hassine M, Van-Pham T, Ragot JL, Philippo C, Farjot G, Noah L, Maniani K, Boutarfa A, Nicolai E, Guillot E, Pruniaux MP, Gussregen S, Engel C, Coutant AL, de Miguel B, Castro A. Discovery of SAR184841, a potent and long-lasting inhibitor of 11beta-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D. Bioorg Med Chem Lett. 2013 Apr 15;23(8):2414-21. doi: 10.1016/j.bmcl.2013.02.018., Epub 2013 Feb 22. PMID:23478147 doi:10.1016/j.bmcl.2013.02.018