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Authors
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J.R.Corte,
T.Fang,
H.Osuna,
D.J.Pinto,
K.A.Rossi,
J.E.Myers,
S.Sheriff,
Z.Lou,
J.J.Zheng,
T.W.Harper,
J.M.Bozarth,
Y.Wu,
J.M.Luettgen,
D.A.Seiffert,
C.P.Decicco,
R.R.Wexler,
M.L.Quan.
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A novel series of macrocyclic FXIa inhibitors was designed based on our lead
acyclic phenyl imidazole chemotype. Our initial macrocycles, which were
double-digit nanomolar FXIa inhibitors, were further optimized with assistance
from utilization of structure-based drug design and ligand bound X-ray crystal
structures. This effort resulted in the discovery of a macrocyclic amide linker
which was found to form a key hydrogen bond with the carbonyl of Leu41 in the
FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa
series, exemplified by compound 16, had a FXIa Ki = 0.16 nM with potent
anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x = 0.27 μM)
and excellent selectivity against the relevant blood coagulation enzymes.
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