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PDBsum entry 3b8r
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References listed in PDB file
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Key reference
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Title
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Evaluation of a series of naphthamides as potent, Orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.
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Authors
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M.M.Weiss,
J.C.Harmange,
A.J.Polverino,
D.Bauer,
L.Berry,
V.Berry,
G.Borg,
J.Bready,
D.Chen,
D.Choquette,
A.Coxon,
T.Demelfi,
N.Doerr,
J.Estrada,
J.Flynn,
R.F.Graceffa,
S.P.Harriman,
S.Kaufman,
D.S.La,
A.Long,
S.Neervannan,
V.F.Patel,
M.Potashman,
K.Regal,
P.M.Roveto,
M.L.Schrag,
C.Starnes,
A.Tasker,
Y.Teffera,
D.A.Whittington,
R.Zanon.
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Ref.
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J Med Chem, 2008,
51,
1668-1680.
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PubMed id
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Abstract
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We have previously shown N-arylnaphthamides can be potent inhibitors of vascular
endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted
naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2
(KDR) with an improved selectivity profile against a panel of tyrosine and
serine/threonine kinases. The inhibitory activity of this series was retained at
the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics
following oral dosing and showed potent inhibition of VEGF-induced angiogenesis
in the rat corneal model. Once-daily oral administration of 22 for 14 days led
to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer
xenografts at doses of 10 and 20 mg/kg, respectively.
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