2chm

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[[Image:2chm.gif|left|200px]]
[[Image:2chm.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 2chm |SIZE=350|CAPTION= <scene name='initialview01'>2chm</scene>, resolution 1.6&Aring;
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The line below this paragraph, containing "STRUCTURE_2chm", creates the "Structure Box" on the page.
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|SITE= <scene name='pdbsite=AC1:Mes+Binding+Site+For+Chain+A'>AC1</scene>
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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=3P4:5-[2-(BUT-3-EN-1-YLOXY)-5-(1-HYDROXYVINYL)PYRIDIN-3-YL]-3-ETHYL-2-(1-ETHYLAZETIDIN-3-YL)-1,2,6,7A-TETRAHYDRO-7H-PYRAZOLO[4,3-D]PYRIMIDIN-7-ONE'>3P4</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=
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or leave the SCENE parameter empty for the default display.
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|GENE=
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|DOMAIN=
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{{STRUCTURE_2chm| PDB=2chm | 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=2chm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2chm OCA], [http://www.ebi.ac.uk/pdbsum/2chm PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2chm RCSB]</span>
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}}
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'''CRYSTAL STRUCTURE OF N2 SUBSTITUTED PYRAZOLO PYRIMIDINONES-A FLIPPED BINDING MODE IN PDE5'''
'''CRYSTAL STRUCTURE OF N2 SUBSTITUTED PYRAZOLO PYRIMIDINONES-A FLIPPED BINDING MODE IN PDE5'''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 22:09:39 2008''
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Revision as of 19:09, 3 May 2008

Image:2chm.gif

Template:STRUCTURE 2chm

CRYSTAL STRUCTURE OF N2 SUBSTITUTED PYRAZOLO PYRIMIDINONES-A FLIPPED BINDING MODE IN PDE5


Overview

Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl -1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dih ydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.

About this Structure

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

Reference

A novel series of potent and selective PDE5 inhibitors with potential for high and dose-independent oral bioavailability., Allerton CM, Barber CG, Beaumont KC, Brown DG, Cole SM, Ellis D, Lane CA, Maw GN, Mount NM, Rawson DJ, Robinson CM, Street SD, Summerhill NW, J Med Chem. 2006 Jun 15;49(12):3581-94. PMID:16759100 Page seeded by OCA on Sat May 3 22:09:39 2008

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