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PDBsum entry 4ztf
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Transferase/DNA/inhibitor
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PDB id
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4ztf
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References listed in PDB file
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Key reference
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Title
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Discovery of 2-Pyridinone aminals: a prodrug strategy to advance a second generation of HIV-1 integrase strand transfer inhibitors.
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Authors
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I.T.Raheem,
A.M.Walji,
D.Klein,
J.M.Sanders,
D.A.Powell,
P.Abeywickrema,
G.Barbe,
A.Bennet,
K.Childers,
M.Christensen,
S.D.Clas,
D.Dubost,
M.Embrey,
J.Grobler,
M.J.Hafey,
T.J.Hartingh,
D.J.Hazuda,
J.T.Kuethe,
J.Mccabe dunn,
M.D.Miller,
K.P.Moore,
A.Nolting,
N.Pajkovic,
S.Patel,
Z.Peng,
V.Rada,
P.Rearden,
J.D.Schreier,
J.Sisko,
T.G.Steele,
J.F.Truchon,
J.Wai,
M.Xu,
P.J.Coleman.
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Ref.
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J Med Chem, 2015,
58,
8154-8165.
[DOI no: ]
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PubMed id
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Abstract
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The search for new molecular constructs that resemble the critical two-metal
binding pharmacophore required for HIV integrase strand transfer inhibition
represents a vibrant area of research within drug discovery. Here we present the
discovery of a new class of HIV integrase strand transfer inhibitors based on
the 2-pyridinone core of MK-0536. These efforts led to the identification of two
lead compounds with excellent antiviral activity and preclinical pharmacokinetic
profiles to support a once-daily human dose prediction. Dose escalating PK
studies in dog revealed significant issues with limited oral absorption and
required an innovative prodrug strategy to enhance the high-dose plasma
exposures of the parent molecules.
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