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PDBsum entry 6w4c
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Oxidoreductase
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PDB id
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6w4c
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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 novel, Potent inhibitors of hydroxy acid oxidase 1 (hao1) using DNA-Encoded chemical library screening.
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Authors
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E.C.Y.Lee,
A.J.Mcriner,
K.E.Georgiadis,
J.Liu,
Z.Wang,
A.D.Ferguson,
B.Levin,
M.Von rechenberg,
C.D.Hupp,
M.I.Monteiro,
A.D.Keefe,
A.Olszewski,
C.J.Eyermann,
P.Centrella,
Y.Liu,
S.Arora,
J.W.Cuozzo,
Y.Zhang,
M.A.Clark,
C.Huguet,
A.Kohlmann.
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Ref.
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J Med Chem, 2021,
64,
6730-6744.
[DOI no: ]
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PubMed id
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Abstract
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Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the
accumulation of toxic oxalate that results from reduced activity of
alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1)
patients. DNA-Encoded Chemical Library (DECL) screening provided two novel
chemical series of potent HAO1 inhibitors, represented by compounds
3-6. Compound 5 was further optimized via various
structure-activity relationship (SAR) exploration methods to 29, a
compound with improved potency and absorption, distribution, metabolism, and
excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic
acid-containing compounds are often poorly permeable and have potential active
glucuronide metabolites, we undertook a brief, initial exploration of acid
replacements with the aim of identifying non-acid-containing HAO1 inhibitors.
Structure-based drug design initiated with Compound 5 led to the
identification of a nonacid inhibitor of HAO1, 31, which has weaker
potency and increased permeability.
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