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4q1n

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Revision as of 08:47, 22 November 2017

Structure-based design of 4-hydroxy-3,5-substituted piperidines as direct renin inhibitors

Structural highlights

4q1n is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	4pyv
Gene:	REN (HUMAN)
Activity:	Renin, with EC number 3.4.23.15
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.

Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors.,Ehara T, Irie O, Kosaka T, Kanazawa T, Breitenstein W, Grosche P, Ostermann N, Suzuki M, Kawakami S, Konishi K, Hitomi Y, Toyao A, Gunji H, Cumin F, Schiering N, Wagner T, Rigel DF, Webb RL, Maibaum J, Yokokawa F ACS Med Chem Lett. 2014 Apr 21;5(7):787-92. doi: 10.1021/ml500137b. eCollection, 2014 Jul 10. PMID:25050166^[3]

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

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
↑ Ehara T, Irie O, Kosaka T, Kanazawa T, Breitenstein W, Grosche P, Ostermann N, Suzuki M, Kawakami S, Konishi K, Hitomi Y, Toyao A, Gunji H, Cumin F, Schiering N, Wagner T, Rigel DF, Webb RL, Maibaum J, Yokokawa F. Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors. ACS Med Chem Lett. 2014 Apr 21;5(7):787-92. doi: 10.1021/ml500137b. eCollection, 2014 Jul 10. PMID:25050166 doi:http://dx.doi.org/10.1021/ml500137b

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4q1n"

@@ Line 3: / Line 3: @@
 <StructureSection load='4q1n' size='340' side='right' caption='[[4q1n]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4q1n]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Q1N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Q1N FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4q1n]] 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=4Q1N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Q1N FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2Y9:(3S,4R,5R)-N-CYCLOPROPYL-N-[(2R)-1-ETHOXY-4-METHYLPENTAN-2-YL]-4-HYDROXY-N-[5-(PROPAN-2-YL)PYRIDIN-2-YL]PIPERIDINE-3,5-DICARBOXAMIDE'>2Y9</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4pyv|4pyv]]</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='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=4q1n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q1n OCA], [http://pdbe.org/4q1n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4q1n RCSB], [http://www.ebi.ac.uk/pdbsum/4q1n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4q1n ProSAT]</span></td></tr>
@@ Line 22: / Line 23: @@
 </div>
 <div class="pdbe-citations 4q1n" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Renin|Renin]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Renin]]
 [[Category: Arcy, A D]]

4q1n

From Proteopedia

Revision as of 08:47, 22 November 2017

Structure-based design of 4-hydroxy-3,5-substituted piperidines as direct renin inhibitors

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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