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PDBsum entry 3k9x
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References listed in PDB file
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Key reference
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Title
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Aroylguanidine-Based factor xa inhibitors: the discovery of bms-344577.
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Authors
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Y.Shi,
C.Li,
S.P.O'Connor,
J.Zhang,
M.Shi,
S.N.Bisaha,
Y.Wang,
D.Sitkoff,
A.T.Pudzianowski,
C.Huang,
H.E.Klei,
K.Kish,
J.Yanchunas,
E.C.Liu,
K.S.Hartl,
S.M.Seiler,
T.E.Steinbacher,
W.A.Schumacher,
K.S.Atwal,
P.D.Stein.
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Ref.
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Bioorg Med Chem Lett, 2009,
19,
6882-6889.
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PubMed id
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Abstract
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We report the design and synthesis of a novel class of N,N'-disubstituted
aroylguanidine-based lactam derivatives as potent and orally active FXa
inhibitors. The structure-activity relationships (SAR) investigation led to the
discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4
nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity
(IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis
of the X-ray crystal structure of compound 22 bound to FXa indicated that the
substituent at the 6-position of the nicotinoyl group of 22 would be
solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity
could focus at this position without affecting FXa potency significantly.
Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the
discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9
nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious
FXa inhibitor with an excellent in vitro liability profile, favorable
pharmacokinetics and pharmacodynamics in animal models.
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