2chm: Difference between revisions

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.

2CHM is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN, MG, 3P4 and MES as [http://en.wikipedia.org/wiki/ligands ligands]. Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2CHM OCA].  

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