View source for 5kos


==Discovery of TAK-272: A Novel, Potent and Orally Active Renin In-hibitor==
<StructureSection load='5kos' size='340' side='right'caption='[[5kos]], [[Resolution|resolution]] 2.41&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5kos]] 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=5KOS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KOS 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]] 2.41&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6VS:2-~{TERT}-BUTYL-4-(3-METHOXYPROPYLAMINO)-~{N}-(2-METHYLPROPYL)-~{N}-[(3~{S},5~{R})-5-MORPHOLIN-4-YLCARBONYLPIPERIDIN-3-YL]PYRIMIDINE-5-CARBOXAMIDE'>6VS</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=5kos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kos OCA], [https://pdbe.org/5kos PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kos RCSB], [https://www.ebi.ac.uk/pdbsum/5kos PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kos ProSAT]</span></td></tr>
</table>
== Disease ==
[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 ==
[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 ==
The aspartic proteinase renin is an attractive target for the treatment of hypertension and cardiovascular/renal disease such as chronic kidney disease and heart failure. We introduced an S1' site binder into the lead compound 1 guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative 10 (1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-yl)carbonylpiper idin-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor. Compound 10 demonstrated good oral bioavailability (BA) and long-lasting efficacy in rats. Compound 10 is currently in clinical trials.

Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor.,Imaeda Y, Tokuhara H, Fukase Y, Kanagawa R, Kajimoto Y, Kusumoto K, Kondo M, Snell G, Behnke CA, Kuroita T ACS Med Chem Lett. 2016 Sep 12;7(10):933-938. eCollection 2016 Oct 13. PMID:27774132<ref>PMID:27774132</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5kos" style="background-color:#fffaf0;"></div>

==See Also==
*[[Renin|Renin]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Behnke CA]]
[[Category: Hideyuki O]]
[[Category: Lane W]]
[[Category: Okada K]]
[[Category: Sang B-C]]
[[Category: Snell GP]]