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PDBsum entry 3hdm
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References listed in PDB file
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Key reference
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Title
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Design and synthesis of orally bioavailable serum and glucocorticoid-Regulated kinase 1 (sgk1) inhibitors.
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Authors
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M.Hammond,
D.G.Washburn,
H.T.Hoang,
S.Manns,
J.S.Frazee,
H.Nakamura,
J.R.Patterson,
W.Trizna,
C.Wu,
L.M.Azzarano,
R.Nagilla,
M.Nord,
R.Trejo,
M.S.Head,
B.Zhao,
A.M.Smallwood,
K.Hightower,
N.J.Laping,
C.G.Schnackenberg,
S.K.Thompson.
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Ref.
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Bioorg Med Chem Lett, 2009,
19,
4441-4445.
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PubMed id
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Abstract
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The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors
4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and
{4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2)
suffer from low DNAUC values in rat, due in part to formation and excretion of
glucuronic acid conjugates. These PK/glucuronidation issues were addressed
either by incorporating a substituent on the 3-phenyl ring ortho to the key
carboxylate functionality of 1 or by substituting on the group in between the
carboxylate and phenyl ring of 2. Three of these analogs have been identified as
having good SGK1 inhibition potency and have DNAUC values suitable for in vivo
testing.
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