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PDBsum entry 3q5h
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Hydrolase/hydrolase inhibitor
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PDB id
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3q5h
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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 vtp-27999, An alkyl amine renin inhibitor with potential for clinical utility.
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Authors
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L.Jia,
R.D.Simpson,
J.Yuan,
Z.Xu,
W.Zhao,
S.Cacatian,
C.M.Tice,
J.Guo,
A.Ishchenko,
S.B.Singh,
Z.Wu,
B.M.Mckeever,
Y.Bukhtiyarov,
J.A.Johnson,
C.P.Doe,
R.K.Harrison,
G.M.Mcgeehan,
L.W.Dillard,
J.J.Baldwin,
D.A.Claremon.
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Ref.
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Acs Med Chem Lett, 2011,
2,
747-751.
[DOI no: ]
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PubMed id
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Abstract
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Structure guided optimization of a series of nonpeptidic alkyl amine renin
inhibitors allowed the rational incorporation of additional polar functionality.
Replacement of the cyclohexylmethyl group occupying the S1 pocket with a
(R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment
point led to the identification of clinical candidate 9. This compound
demonstrated excellent selectivity over related and unrelated off-targets,
>15% oral bioavailability in three species, oral efficacy in a double
transgenic rat model of hypertension, and good exposure in humans.
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