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PDBsum entry 4tot
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Isomerase/isomerase inhibitor
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PDB id
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4tot
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References listed in PDB file
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Key reference
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Title
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Potent nonimmunosuppressive cyclophilin inhibitors with improved pharmaceutical properties and decreased transporter inhibition.
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Authors
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J.Fu,
M.Tjandra,
C.Becker,
D.Bednarczyk,
M.Capparelli,
R.Elling,
I.Hanna,
R.Fujimoto,
M.Furegati,
S.Karur,
T.Kasprzyk,
M.Knapp,
K.Leung,
X.Li,
P.Lu,
W.Mergo,
C.Miault,
S.Ng,
D.Parker,
Y.Peng,
S.Roggo,
A.Rivkin,
R.L.Simmons,
M.Wang,
B.Wiedmann,
A.H.Weiss,
L.Xiao,
L.Xie,
W.Xu,
A.Yifru,
S.Yang,
B.Zhou,
Z.K.Sweeney.
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Ref.
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J Med Chem, 2014,
57,
8503-8516.
[DOI no: ]
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PubMed id
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Abstract
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Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the
treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A,
and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and
other important drug transporters. Reduction of the side chain hydrophobicity of
the P4 residue preserves cyclophilin binding and antiviral potency while
decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a
less potent transporter inhibitor relative to previously described cyclosporins,
retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic
profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is
reported.
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