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==Free-Wilson and Structural Approaches to Co-optimising Human and Rodent Isoform Potency for 11b-Hydroxysteroid Dehydrogenase Type 1 11b-HSD1 Inhibitors== | |||
<StructureSection load='4bb5' size='340' side='right' caption='[[4bb5]], [[Resolution|resolution]] 2.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4bb5]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BB5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BB5 FirstGlance]. <br> | |||
==Disease== | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HD2:4-CYCLOPENTYL-N-[(1S,3R)-5-OXIDANYL-2-ADAMANTYL]-2-[[(3S)-OXOLAN-3-YL]AMINO]PYRIMIDINE-5-CARBOXAMIDE'>HD2</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1xu7|1xu7]], [[1xu9|1xu9]], [[2bel|2bel]], [[4bb6|4bb6]]</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=4bb5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bb5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bb5 RCSB], [http://www.ebi.ac.uk/pdbsum/4bb5 PDBsum]</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). | [[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 == | |||
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 >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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: 11-beta-hydroxysteroid dehydrogenase]] | [[Category: 11-beta-hydroxysteroid dehydrogenase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Bennett, S N.L | [[Category: Bennett, S N.L]] | ||
[[Category: Bodin, C | [[Category: Bodin, C]] | ||
[[Category: Donald, C S | [[Category: Donald, C S]] | ||
[[Category: Goldberg, F W | [[Category: Goldberg, F W]] | ||
[[Category: Groombridge, S D | [[Category: Groombridge, S D]] | ||
[[Category: Gutierrez, P Morentin | [[Category: Gutierrez, P Morentin]] | ||
[[Category: Gyte, A C | [[Category: Gyte, A C]] | ||
[[Category: Leach, A G | [[Category: Leach, A G]] | ||
[[Category: Scott, J S | [[Category: Scott, J S]] | ||
[[Category: Snelson, W L | [[Category: Snelson, W L]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
Revision as of 16:04, 5 January 2015
Free-Wilson and Structural Approaches to Co-optimising Human and Rodent Isoform Potency for 11b-Hydroxysteroid Dehydrogenase Type 1 11b-HSD1 InhibitorsFree-Wilson and Structural Approaches to Co-optimising Human and Rodent Isoform Potency for 11b-Hydroxysteroid Dehydrogenase Type 1 11b-HSD1 Inhibitors
Structural highlights
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 PubMed11beta-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 >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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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