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PDBsum entry 1ld8
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency.
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Authors
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I.M.Bell,
S.N.Gallicchio,
M.Abrams,
L.S.Beese,
D.C.Beshore,
H.Bhimnathwala,
M.J.Bogusky,
C.A.Buser,
J.C.Culberson,
J.Davide,
M.Ellis-Hutchings,
C.Fernandes,
J.B.Gibbs,
S.L.Graham,
K.A.Hamilton,
G.D.Hartman,
D.C.Heimbrook,
C.F.Homnick,
H.E.Huber,
J.R.Huff,
K.Kassahun,
K.S.Koblan,
N.E.Kohl,
R.B.Lobell,
J.J.Lynch,
R.Robinson,
A.D.Rodrigues,
J.S.Taylor,
E.S.Walsh,
T.M.Williams,
C.B.Zartman.
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Ref.
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J Med Chem, 2002,
45,
2388-2409.
[DOI no: ]
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PubMed id
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Abstract
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A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors
(FTIs) has been synthesized. Compared with previously described linear
3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined
improved pharmacokinetic properties with a reduced potential for side effects.
In dogs, oral bioavailability was good to excellent, and increases in plasma
half-life were due to attenuated clearance. It was observed that in vivo
clearance correlated with the flexibility of the molecules and this concept
proved useful in the design of FTIs that exhibited low clearance, such as FTI
78. X-ray crystal structures of compounds 49 and 66 complexed with
farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they
provide details of the key interactions in such ternary complexes. Optimization
of this 3-aminopyrrolidinone series of compounds led to significant increases in
potency, providing 83 and 85, the most potent inhibitors of FTase in cells
described to date.
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