4rz1

From Proteopedia

(Difference between revisions)

Revision as of 14:04, 26 March 2015

RENIN IN COMPLEXED WITH (3S,4S)-4-({[4-methoxy-3-(3-methoxypropoxy)benzoyl](propan-2-yl)amino}methyl)pyrrolidin-3-yl benzylcarbamate INHIBITOR

Structural highlights

4rz1 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Activity:	Renin, with EC number 3.4.23.15
Resources:	FirstGlance, OCA, RCSB, PDBsum

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

Inhibition of the aspartyl protease renin is considered as an efficient approach for treating hypertension. Lately, we described the discovery of a novel class of direct renin inhibitors which comprised a pyrrolidine scaffold (e.g., 2). Based on the X-ray structure of the lead compound 2 bound to renin we predicted that optimization of binding interactions to the prime site could offer an opportunity to further expand the scope of this chemotype. Pyrrolidine-based inhibitors were synthesized in which the prime site moieties are linked to the pyrrolidine core through an oxygen atom, resulting in an ether or a carbamate linker subseries. Especially the carbamate derivatives showed a pronounced increase in in vitro potency compared to 2. Here we report the structure-activity relationship of both subclasses and demonstrate blood pressure lowering effects for an advanced prototype in a hypertensive double-transgenic rat model after oral dosing.

trans-3,4-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part II: Prime site exploration using an oxygen linker.,Sellner H, Cottens S, Cumin F, Ehrhardt C, Kosaka T, Lorthiois E, Ostermann N, Webb RL, Rigel DF, Wagner T, Maibaum J Bioorg Med Chem Lett. 2015 Feb 23. pii: S0960-894X(15)00147-X. doi:, 10.1016/j.bmcl.2015.02.040. PMID:25754490^[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
↑ Sellner H, Cottens S, Cumin F, Ehrhardt C, Kosaka T, Lorthiois E, Ostermann N, Webb RL, Rigel DF, Wagner T, Maibaum J. trans-3,4-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part II: Prime site exploration using an oxygen linker. Bioorg Med Chem Lett. 2015 Feb 23. pii: S0960-894X(15)00147-X. doi:, 10.1016/j.bmcl.2015.02.040. PMID:25754490 doi:http://dx.doi.org/10.1016/j.bmcl.2015.02.040

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/4rz1"

Categories: Renin | Ostermann, N | Hydrolase | Hydrolase-hydrolase inhibitor complex

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+==RENIN IN COMPLEXED WITH (3S,4S)-4-({[4-methoxy-3-(3-methoxypropoxy)benzoyl](propan-2-yl)amino}methyl)pyrrolidin-3-yl benzylcarbamate INHIBITOR==
+<StructureSection load='4rz1' size='340' side='right' caption='[[4rz1]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4rz1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RZ1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RZ1 FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3ZN:(3S,4S)-4-({[4-METHOXY-3-(3-METHOXYPROPOXY)BENZOYL](PROPAN-2-YL)AMINO}METHYL)PYRROLIDIN-3-YL+BENZYLCARBAMATE'>3ZN</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=4rz1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rz1 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rz1 RCSB], [http://www.ebi.ac.uk/pdbsum/4rz1 PDBsum]</span></td></tr>
+</table>
+== 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>
+== 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.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Inhibition of the aspartyl protease renin is considered as an efficient approach for treating hypertension. Lately, we described the discovery of a novel class of direct renin inhibitors which comprised a pyrrolidine scaffold (e.g., 2). Based on the X-ray structure of the lead compound 2 bound to renin we predicted that optimization of binding interactions to the prime site could offer an opportunity to further expand the scope of this chemotype. Pyrrolidine-based inhibitors were synthesized in which the prime site moieties are linked to the pyrrolidine core through an oxygen atom, resulting in an ether or a carbamate linker subseries. Especially the carbamate derivatives showed a pronounced increase in in vitro potency compared to 2. Here we report the structure-activity relationship of both subclasses and demonstrate blood pressure lowering effects for an advanced prototype in a hypertensive double-transgenic rat model after oral dosing.
-The entry 4rz1 is ON HOLD  until Paper Publication
+trans-3,4-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part II: Prime site exploration using an oxygen linker.,Sellner H, Cottens S, Cumin F, Ehrhardt C, Kosaka T, Lorthiois E, Ostermann N, Webb RL, Rigel DF, Wagner T, Maibaum J Bioorg Med Chem Lett. 2015 Feb 23. pii: S0960-894X(15)00147-X. doi:, 10.1016/j.bmcl.2015.02.040. PMID:25754490<ref>PMID:25754490</ref>
-Authors: Ostermann, N.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-Description:
+== References ==
-[[Category: Unreleased Structures]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Renin]]
 [[Category: Ostermann, N]]
+[[Category: Hydrolase]]
+[[Category: Hydrolase-hydrolase inhibitor complex]]

4rz1

From Proteopedia

Revision as of 14:04, 26 March 2015

RENIN IN COMPLEXED WITH (3S,4S)-4-({[4-methoxy-3-(3-methoxypropoxy)benzoyl](propan-2-yl)amino}methyl)pyrrolidin-3-yl benzylcarbamate INHIBITOR

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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