5pgz

<StructureSection load='5pgz' size='340' side='right' caption='[[5pgz]], [[Resolution|resolution]] 2.90&Aring;' scene=''>

<table><tr><td colspan='2'>[[5pgz]] is a 2 chain structure. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5PGZ FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8KG:2-[(5R,7S)-6-HYDROXY-2-PHENYLADAMANTAN-2-YL]-1-(3-HYDROXYAZETIDIN-1-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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/11-beta-hydroxysteroid_dehydrogenase 11-beta-hydroxysteroid dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.146 1.1.1.146] </span></td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5pgz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5pgz OCA], [http://pdbe.org/5pgz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5pgz RCSB], [http://www.ebi.ac.uk/pdbsum/5pgz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5pgz ProSAT]</span></td></tr>

[[http://www.uniprot.org/uniprot/DHI1_MOUSE DHI1_MOUSE]] Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone.

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.

 

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== References ==

[[Category: 11-beta-hydroxysteroid dehydrogenase]]

[[Category: Sheriff, S]]

[[Category: 11b-hsd1]]

[[Category: Sdr]]