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PDBsum entry 1v79
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References listed in PDB file
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Key reference
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Title
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Structure-Based design and synthesis of non-Nucleoside, Potent, And orally bioavailable adenosine deaminase inhibitors.
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Authors
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T.Terasaka,
H.Okumura,
K.Tsuji,
T.Kato,
I.Nakanishi,
T.Kinoshita,
Y.Kato,
M.Kuno,
N.Seki,
Y.Naoe,
T.Inoue,
K.Tanaka,
K.Nakamura.
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Ref.
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J Med Chem, 2004,
47,
2728-2731.
[DOI no: ]
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PubMed id
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Abstract
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We disclose optimization efforts based on the novel non-nucleoside adenosine
deaminase (ADA) inhibitor, 4 (K(i) = 680 nM). Structure-based drug design
utilizing the crystal structure of the 4/ADA complex led to discovery of 5 (K(i)
= 11 nM, BA = 30% in rats). Furthermore, from metabolic considerations, we
discovered two inhibitors with improved oral bioavailability [6 (K(i) = 13 nM,
BA = 44%) and 7 (K(i) = 9.8 nM, BA = 42%)]. 6 demonstrated in vivo efficacy in
models of inflammation and lymphoma.
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