2chm

Crystal structure of N2 substituted pyrazolo pyrimidinones - a flipped binding mode in PDE5

spinqualitylabelsall models 2chm, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2chm is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 3P4, MES, MG, ZN Related: 1f0j, 1jp1, 1jp2, 1ro6, 1ro9, 1ror, 1rkp, 1t9r, 1t9s, 1tb5, 1tbf, 1udt, 1udu, 1uho, 1xlx, 1xlz, 1xm4, 1xm6, 1xmu, 1xmy, 1xn0, 1xos, 1xot, 1xoz, 1xp0, 1y2h, 1y2j Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [PDE5A_HUMAN] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphodiesterase 3D structures

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