2oag

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[[Image:2oag.jpg|left|200px]]
[[Image:2oag.jpg|left|200px]]
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{{Structure
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<!--
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|PDB= 2oag |SIZE=350|CAPTION= <scene name='initialview01'>2oag</scene>, resolution 2.300&Aring;
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The line below this paragraph, containing "STRUCTURE_2oag", creates the "Structure Box" on the page.
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|SITE=
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=DLI:(3R,4S)-1-{6-[3-(METHYLSULFONYL)PHENYL]PYRIMIDIN-4-YL}-4-(2,4,5-TRIFLUOROPHENYL)PYRROLIDIN-3-AMINE'>DLI</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Dipeptidyl-peptidase_IV Dipeptidyl-peptidase IV], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.14.5 3.4.14.5] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE= DPP4, ADCP2, CD26 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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-->
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|DOMAIN=
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{{STRUCTURE_2oag| PDB=2oag | SCENE= }}
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2oag FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2oag OCA], [http://www.ebi.ac.uk/pdbsum/2oag PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2oag RCSB]</span>
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}}
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'''Crystal structure of human dipeptidyl peptidase IV (DPPIV) with pyrrolidine-constrained phenethylamine 29g'''
'''Crystal structure of human dipeptidyl peptidase IV (DPPIV) with pyrrolidine-constrained phenethylamine 29g'''
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[[Category: Longenecker, K L.]]
[[Category: Longenecker, K L.]]
[[Category: Stewart, K D.]]
[[Category: Stewart, K D.]]
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[[Category: hydrolase]]
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[[Category: Hydrolase]]
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[[Category: inhibitor complex]]
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[[Category: Inhibitor complex]]
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[[Category: serine-peptidase]]
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[[Category: Serine-peptidase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 10:31:21 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:15:01 2008''
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Revision as of 07:31, 4 May 2008

Image:2oag.jpg

Template:STRUCTURE 2oag

Crystal structure of human dipeptidyl peptidase IV (DPPIV) with pyrrolidine-constrained phenethylamine 29g


Overview

A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.

About this Structure

2OAG is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit., Backes BJ, Longenecker K, Hamilton GL, Stewart K, Lai C, Kopecka H, von Geldern TW, Madar DJ, Pei Z, Lubben TH, Zinker BA, Tian Z, Ballaron SJ, Stashko MA, Mika AK, Beno DW, Kempf-Grote AJ, Black-Schaefer C, Sham HL, Trevillyan JM, Bioorg Med Chem Lett. 2007 Apr 1;17(7):2005-12. Epub 2007 Jan 19. PMID:17276063 Page seeded by OCA on Sun May 4 10:31:21 2008

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