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PDBsum entry 2b55
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References listed in PDB file
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Key reference
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Title
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Synthesis and evaluation of indenopyrazoles as cyclin-Dependent kinase inhibitors. 3. Structure activity relationships at c3(1,2).
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Authors
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E.W.Yue,
C.A.Higley,
S.V.Dimeo,
D.J.Carini,
D.A.Nugiel,
C.Benware,
P.A.Benfield,
C.R.Burton,
S.Cox,
R.H.Grafstrom,
D.M.Sharp,
L.M.Sisk,
J.F.Boylan,
J.K.Muckelbauer,
A.M.Smallwood,
H.Chen,
C.H.Chang,
S.P.Seitz,
G.L.Trainor.
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Ref.
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J Med Chem, 2002,
45,
5233-5248.
[DOI no: ]
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PubMed id
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Abstract
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The identification of indeno[1,2-c]pyrazol-4-ones as inhibitors of
cyclin-dependent kinases (CDKs) has led to the discovery of a series of novel
and potent compounds. Herein, we report the effects of substitutions at C3 of
the indeno[1,2-c]pyrazol-4-one core with alkyls, heterocycles, and substituted
phenyls. Substitutions at the para position of the phenyl ring at C3 were
generally well-tolerated; however, larger groups were generally inactive. For
alkyls directly attached to C3, longer chain substituents were not tolerated;
however, shorter alkyl groups and cyclic alkyls were acceptable. In general, the
heterocycles at C3 gave the most potent analogues. One such heterocycle, 24j,
was examined in detail and was determined to have a biological profile
consistent with CDK inhibition. An X-ray crystal structure of one of the alkyl
compounds, 13q, complexed with CDK2 was determined and showed the inhibitor
residing in the adenosine 5'-triphosphate pocket of the enzyme.
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