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| | ==Human renin in complex with compound 5== | | ==Human renin in complex with compound 5== |
| - | <StructureSection load='3vuc' size='340' side='right' caption='[[3vuc]], [[Resolution|resolution]] 2.60Å' scene=''> | + | <StructureSection load='3vuc' size='340' side='right'caption='[[3vuc]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3vuc]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VUC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3VUC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3vuc]] 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=3VUC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VUC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HHE:(2R,4S,5S)-5-AMINO-6-[4-(2-CHLOROPHENYL)-2,2-DIMETHYL-5-OXOPIPERAZIN-1-YL]-2-ETHYL-4-HYDROXY-N-[(1R,2S,3S,5S,7S)-5-HYDROXYTRICYCLO[3.3.1.1~3,7~]DEC-2-YL]HEXANAMIDE'>HHE</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3vsx|3vsx]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HHE:(2R,4S,5S)-5-AMINO-6-[4-(2-CHLOROPHENYL)-2,2-DIMETHYL-5-OXOPIPERAZIN-1-YL]-2-ETHYL-4-HYDROXY-N-[(1R,2S,3S,5S,7S)-5-HYDROXYTRICYCLO[3.3.1.1~3,7~]DEC-2-YL]HEXANAMIDE'>HHE</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">REN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3vuc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vuc OCA], [https://pdbe.org/3vuc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3vuc RCSB], [https://www.ebi.ac.uk/pdbsum/3vuc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3vuc ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Renin Renin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.15 3.4.23.15] </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=3vuc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vuc OCA], [http://pdbe.org/3vuc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3vuc RCSB], [http://www.ebi.ac.uk/pdbsum/3vuc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3vuc ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN]] Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM:[http://omim.org/entry/267430 267430]]. RTD is an autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype).<ref>PMID:16116425</ref> Defects in REN are the cause of familial juvenile hyperuricemic nephropathy type 2 (HNFJ2) [MIM:[http://omim.org/entry/613092 613092]]. It is a renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia.<ref>PMID:19664745</ref> | + | [https://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN] Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM:[https://omim.org/entry/267430 267430]. RTD is an autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype).<ref>PMID:16116425</ref> Defects in REN are the cause of familial juvenile hyperuricemic nephropathy type 2 (HNFJ2) [MIM:[https://omim.org/entry/613092 613092]. It is a renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia.<ref>PMID:19664745</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN]] Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney. | + | [https://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN] Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney. |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | A novel orally bioavailable renin inhibitor, DS-8108b (5), showing potent renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including renin inhibitory activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human renin (IC50 = 0.9 nM) and human and monkey PRA (IC50 = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h. |
| | + | |
| | + | Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor.,Nakamura Y, Fujimoto T, Ogawa Y, Sugita C, Miyazaki S, Tamaki K, Takahashi M, Matsui Y, Nagayama T, Manabe K, Mizuno M, Masubuchi N, Chiba K, Nishi T ACS Med Chem Lett. 2012 Aug 18;3(9):754-8. doi: 10.1021/ml300168e. eCollection, 2012 Sep 13. PMID:24900544<ref>PMID:24900544</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 3vuc" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Renin|Renin]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Renin]] | + | [[Category: Large Structures]] |
| - | [[Category: Hanzawa, H]] | + | [[Category: Hanzawa H]] |
| - | [[Category: Matsui, Y]] | + | [[Category: Matsui Y]] |
| - | [[Category: Takahashi, M]] | + | [[Category: Takahashi M]] |
| - | [[Category: Aspartyl protease]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Hypertension]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Ra]]
| + | |
| Structural highlights
Disease
RENI_HUMAN Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM:267430. RTD is an autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype).[1] Defects in REN are the cause of familial juvenile hyperuricemic nephropathy type 2 (HNFJ2) [MIM:613092. It is a renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia.[2]
Function
RENI_HUMAN Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney.
Publication Abstract from PubMed
A novel orally bioavailable renin inhibitor, DS-8108b (5), showing potent renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including renin inhibitory activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human renin (IC50 = 0.9 nM) and human and monkey PRA (IC50 = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.
Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor.,Nakamura Y, Fujimoto T, Ogawa Y, Sugita C, Miyazaki S, Tamaki K, Takahashi M, Matsui Y, Nagayama T, Manabe K, Mizuno M, Masubuchi N, Chiba K, Nishi T ACS Med Chem Lett. 2012 Aug 18;3(9):754-8. doi: 10.1021/ml300168e. eCollection, 2012 Sep 13. PMID:24900544[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gribouval O, Gonzales M, Neuhaus T, Aziza J, Bieth E, Laurent N, Bouton JM, Feuillet F, Makni S, Ben Amar H, Laube G, Delezoide AL, Bouvier R, Dijoud F, Ollagnon-Roman E, Roume J, Joubert M, Antignac C, Gubler MC. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet. 2005 Sep;37(9):964-8. Epub 2005 Aug 14. PMID:16116425 doi:ng1623
- ↑ Zivna M, Hulkova H, Matignon M, Hodanova K, Vylet'al P, Kalbacova M, Baresova V, Sikora J, Blazkova H, Zivny J, Ivanek R, Stranecky V, Sovova J, Claes K, Lerut E, Fryns JP, Hart PS, Hart TC, Adams JN, Pawtowski A, Clemessy M, Gasc JM, Gubler MC, Antignac C, Elleder M, Kapp K, Grimbert P, Bleyer AJ, Kmoch S. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure. Am J Hum Genet. 2009 Aug;85(2):204-13. Epub 2009 Aug 6. PMID:19664745 doi:10.1016/j.ajhg.2009.07.010
- ↑ Nakamura Y, Fujimoto T, Ogawa Y, Sugita C, Miyazaki S, Tamaki K, Takahashi M, Matsui Y, Nagayama T, Manabe K, Mizuno M, Masubuchi N, Chiba K, Nishi T. Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor. ACS Med Chem Lett. 2012 Aug 18;3(9):754-8. doi: 10.1021/ml300168e. eCollection, 2012 Sep 13. PMID:24900544 doi:http://dx.doi.org/10.1021/ml300168e
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