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'''Unreleased structure'''


The entry 5pgv is ON HOLD  until Paper Publication
==CRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 1-(3-HYDROXYAZETIDIN-1-YL)-2-[(2S,5R)-2-(4-FLUOROPHENYL)-5-METHOXYADAMANTAN-2-YL]ETHAN-1-ONE==
<StructureSection load='5pgv' size='340' side='right' caption='[[5pgv]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5pgv]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5PGV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5PGV FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8K7:1-(3-HYDROXYAZETIDIN-1-YL)-2-[(2S,5R)-2-(4-FLUOROPHENYL)-5-METHOXYADAMANTAN-2-YL]ETHAN-1-ONE'>8K7</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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=5pgv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5pgv OCA], [http://pdbe.org/5pgv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5pgv RCSB], [http://www.ebi.ac.uk/pdbsum/5pgv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5pgv ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/DHI1_HUMAN DHI1_HUMAN]] Defects in HSD11B1 are a cause of cortisone reductase deficiency (CRD) [MIM:[http://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 ==
[[http://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 ==
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.


Authors: Sheriff, S.
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>


Description: CRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 1-(3-HYDROXYAZETIDIN-1-YL)-2-[(2S,5R)-2-(4-FLUOROPHENYL)-5-METHOXYADAMANTAN-2-YL]ETHAN-1-ONE
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 5pgv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: 11-beta-hydroxysteroid dehydrogenase]]
[[Category: Sheriff, S]]
[[Category: Sheriff, S]]
[[Category: 11b-hsd1]]
[[Category: Dehydrogenase]]
[[Category: Hydroxysteroid]]
[[Category: Inhibitor]]
[[Category: Oxidoreductase-oxidoreductase inhibi complex]]
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
[[Category: Sdr]]

Revision as of 09:13, 1 November 2017

CRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 1-(3-HYDROXYAZETIDIN-1-YL)-2-[(2S,5R)-2-(4-FLUOROPHENYL)-5-METHOXYADAMANTAN-2-YL]ETHAN-1-ONECRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 1-(3-HYDROXYAZETIDIN-1-YL)-2-[(2S,5R)-2-(4-FLUOROPHENYL)-5-METHOXYADAMANTAN-2-YL]ETHAN-1-ONE

Structural highlights

5pgv is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Activity:11-beta-hydroxysteroid dehydrogenase, with EC number 1.1.1.146
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

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 >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[1]

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

References

  1. ↑ 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. 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. J Med Chem. 2017 Jun 22;60(12):4932-4948. doi: 10.1021/acs.jmedchem.7b00211. Epub, 2017 Jun 5. PMID:28537398 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00211

5pgv, resolution 2.35Å

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