View source for 4bb6


==Free-Wilson and Structural Approaches to Co-optimising Human and Rodent Isoform Potency for 11b-Hydroxysteroid Dehydrogenase Type 1 11b-HSD1 Inhibitors==
<StructureSection load='4bb6' size='340' side='right'caption='[[4bb6]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4bb6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BB6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BB6 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]] 2.55&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=HD1:6-(4-METHYLPIPERAZIN-1-YL)-N-[(1R,3S)-5-OXIDANYL-2-ADAMANTYL]-2-PROPYLSULFANYL-PYRIDINE-3-CARBOXAMIDE'>HD1</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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=4bb6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bb6 OCA], [https://pdbe.org/4bb6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bb6 RCSB], [https://www.ebi.ac.uk/pdbsum/4bb6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bb6 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/DHI1_HUMAN DHI1_HUMAN] Defects in HSD11B1 are a cause of cortisone reductase deficiency (CRD) [MIM:[https://omim.org/entry/604931 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 ==
[https://www.uniprot.org/uniprot/DHI1_HUMAN 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).
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
11beta-Hydroxysteroid dehydrogenase 1 (11beta-HSD1) has been a target of intensive research effort across the pharmaceutical industry, due to its potential for the treatment of type II diabetes and other elements of the metabolic syndrome. In order to demonstrate the value of 11beta-HSD1 in pre-clinical models we required inhibitors with good potency against both human and rodent isoforms. Herein we describe our efforts to understand how to co-optimize human and murine potency within the (5-hydroxy-2-adamantyl)-pyrimidine-5-carboxamide series. Two approaches are described - a data driven (Free-Wilson) analysis and a structure-based design approach. The conclusions from these approaches were used to inform an efficient campaign to design compounds with consistently good human/murine potency within a logD7.4 range of 1-3. Compounds 20 and 26 demonstrated good rodent PK, which allowed us to demonstrate a PK/PD relationship in rat and mouse. We then evaluated 26 against glycaemic and bodyweight endpoints in murine disease models, where it demonstrated glucose and bodyweight efficacy at 300 mg/kg/day but only bodyweight efficacy at 50 mg/kg/day, despite providing &gt;90% target engagement in the liver.

Free-Wilson and Structural Approaches to Co-optimising Human and Rodent Isoform Potency for 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1) Inhibitors.,Goldberg FW, Leach AG, Scott JS, Snelson W, Groombridge S, Donald C, Bennett S, Bodin C, Gutierrez PM, Gyte A J Med Chem. 2012 Nov 16. PMID:23153367<ref>PMID:23153367</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4bb6" style="background-color:#fffaf0;"></div>

==See Also==
*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bennett SNL]]
[[Category: Bodin C]]
[[Category: Donald CS]]
[[Category: Goldberg FW]]
[[Category: Groombridge SD]]
[[Category: Gyte AC]]
[[Category: Leach AG]]
[[Category: Morentin Gutierrez P]]
[[Category: Scott JS]]
[[Category: Snelson WL]]