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PDBsum entry 2chm
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References listed in PDB file
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Key reference
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Title
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A novel series of potent and selective pde5 inhibitors with potential for high and dose-Independent oral bioavailability.
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Authors
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C.M.Allerton,
C.G.Barber,
K.C.Beaumont,
D.G.Brown,
S.M.Cole,
D.Ellis,
C.A.Lane,
G.N.Maw,
N.M.Mount,
D.J.Rawson,
C.M.Robinson,
S.D.Street,
N.W.Summerhill.
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Ref.
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J Med Chem, 2006,
49,
3581-3594.
[DOI no: ]
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PubMed id
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Abstract
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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-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
(2) was selected for progression into the clinic.
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