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Authors
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J.R.Corte,
T.Fang,
D.J.Pinto,
M.J.Orwat,
A.R.Rendina,
J.M.Luettgen,
K.A.Rossi,
A.Wei,
V.Ramamurthy,
J.E.Myers,
S.Sheriff,
R.Narayanan,
T.W.Harper,
J.J.Zheng,
Y.X.Li,
D.A.Seiffert,
R.R.Wexler,
M.L.Quan.
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Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the
P2 prime, P1, and scaffold regions. This work resulted in the discovery of the
methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced
the number of H-bond donors, and improved the physicochemical properties
compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified
as a potent and selective FXIa inhibitor that was orally bioavailable.
Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral
p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a
significant improvement in oral bioavailability compared to the previously
reported imidazole (S)-23. Additional improvements in FXIa binding affinity,
while maintaining oral bioavailability, was achieved by replacing the pyridine
scaffold with either a regioisomeric pyridine or pyrimidine ring system.
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