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PDBsum entry 1uml
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Contents |
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* Residue conservation analysis
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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, Synthesis, And structure-Activity relationship studies of novel non-Nucleoside adenosine deaminase inhibitors.
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Authors
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T.Terasaka,
T.Kinoshita,
M.Kuno,
N.Seki,
K.Tanaka,
I.Nakanishi.
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Ref.
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J Med Chem, 2004,
47,
3730-3743.
[DOI no: ]
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PubMed id
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Abstract
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We disclose herein optimization efforts around the novel, highly potent
non-nucleoside adenosine deaminase (ADA) inhibitor,
1-[(R)-1-hydroxy-4-(6-(3-(1-methylbenzimidazol-2-yl)propionylamino)indol-1-yl)-2-butyl]imidazole-4-carboxamide
1 (K(i)= 7.7 nM), which we recently reported. Structure-based drug design (SBDD)
utilizing the crystal structure of the 1/ADA complex was performed in order to
obtain structure-activity relationships (SAR) for this type of compound
rationally and effectively. To utilize the newly formed hydrophobic space (F2),
replacement of the benzimidazole ring of 1 with a n-propyl chain (4b) or a
simple phenyl ring (4c) was tolerated in terms of binding activity, and the
length of the methylene-spacer was shown to be optimal at two or three.
Replacement of an amide with an ether as a linker was also well tolerated in
terms of binding activity and moreover improved the oral absorption (6a and 6b).
Finally, transformation of indol-1-yl to indol-3-yl resulted in discovery of a
novel highly potent and orally bioavailable ADA inhibitor,
1-[(R)-4-(5-(3-(4-chlorophenyl)propoxy)-1-methylindol-3-yl)-1-hydroxy-2-butyl]imidazole-4-carboxamide
8c.
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