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PDBsum entry 2uzt
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References listed in PDB file
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Key reference
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Title
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Syntheses of potent, Selective, And orally bioavailable indazole-Pyridine series of protein kinase b/akt inhibitors with reduced hypotension.
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Authors
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G.D.Zhu,
V.B.Gandhi,
J.Gong,
S.Thomas,
K.W.Woods,
X.Song,
T.Li,
R.B.Diebold,
Y.Luo,
X.Liu,
R.Guan,
V.Klinghofer,
E.F.Johnson,
J.Bouska,
A.Olson,
K.C.Marsh,
V.S.Stoll,
M.Mamo,
J.Polakowski,
T.J.Campbell,
R.L.Martin,
G.A.Gintant,
T.D.Penning,
Q.Li,
S.H.Rosenberg,
V.L.Giranda.
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Ref.
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J Med Chem, 2007,
50,
2990-3003.
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PubMed id
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Abstract
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Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally
bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While
promising efficacy was observed in vivo, this compound showed effects on
depolarization of Purkinje fibers in an in vitro assay and CV hypotension in
vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80%
homology with Akt in the kinase domain, our efforts have focused on
structure-activity relationship (SAR) studies of the phenyl moiety, in an
attempt to address the cardiovascular liability and further improve the Akt
potency. A novel and efficient synthetic route toward diversely substituted
phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine
ring-opening reaction as the key step. To improve the selectivity of these Akt
inhibitors over other protein kinases, a nitrogen atom was incorporated into
selected phenyl analogues of 7 at the C-6 position of the methyl indazole
scaffold. These modifications resulted in the discovery of inhibitor 37c with
greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular
safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt
inhibitors will be discussed.
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