View source for 5pgz


==CRYSTAL STRUCTURE OF MURINE 11BETA- HYDROXYSTEROIDDEHYDROGENASE COMPLEXED WITH 2-[(5R,7S)-6-HYDROXY-2-PHENYLADAMANTAN-2-YL]-1-(3-HYDROXYAZETIDIN-1-YL)ETHAN-1-ONE (BMS-816336)==
<StructureSection load='5pgz' size='340' side='right'caption='[[5pgz]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5pgz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5PGZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5PGZ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8KG:1-(3-hydroxyazetidin-1-yl)-2-[(1R,2S,3S,5R,6S,7S)-6-hydroxy-2-phenyltricyclo[3.3.1.1~3,7~]decan-2-yl]ethan-1-one'>8KG</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5pgz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5pgz OCA], [https://pdbe.org/5pgz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5pgz RCSB], [https://www.ebi.ac.uk/pdbsum/5pgz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5pgz ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DHI1_MOUSE DHI1_MOUSE] Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme (IC50 3.0 nM) with &gt;10000-fold selectivity over human 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11beta-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.

Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3'-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitor.,Ye XY, Chen SY, Wu S, Yoon DS, Wang H, Hong Z, O'Connor SP, Li J, Li JJ, Kennedy LJ, Walker SJ, Nayeem A, Sheriff S, Camac DM, Ramamurthy V, Morin PE, Zebo R, Taylor JR, Morgan NN, Ponticiello RP, Harrity T, Apedo A, Golla R, Seethala R, Wang M, Harper TW, Sleczka BG, He B, Kirby M, Leahy DK, Li J, Hanson RL, Guo Z, Li YX, DiMarco JD, Scaringe R, Maxwell B, Moulin F, Barrish JC, Gordon DA, Robl JA J Med Chem. 2017 Jun 22;60(12):4932-4948. doi: 10.1021/acs.jmedchem.7b00211. Epub, 2017 Jun 5. PMID:28537398<ref>PMID:28537398</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5pgz" style="background-color:#fffaf0;"></div>

==See Also==
*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Sheriff S]]