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PDBsum entry 4ty6
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Hydrolase/hydrolase inhibitor
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PDB id
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4ty6
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References listed in PDB file
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Key reference
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Title
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Phenylimidazoles as potent and selective inhibitors of coagulation factor xia with in vivo antithrombotic activity.
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Authors
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J.J.Hangeland,
T.J.Friends,
K.A.Rossi,
J.M.Smallheer,
C.Wang,
Z.Sun,
J.R.Corte,
T.Fang,
P.C.Wong,
A.R.Rendina,
F.A.Barbera,
J.M.Bozarth,
J.M.Luettgen,
C.A.Watson,
G.Zhang,
A.Wei,
V.Ramamurthy,
P.E.Morin,
G.S.Bisacchi,
S.Subramaniam,
P.Arunachalam,
A.Mathur,
D.A.Seiffert,
R.R.Wexler,
M.L.Quan.
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Ref.
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J Med Chem, 2014,
57,
9915-9932.
[DOI no: ]
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PubMed id
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Abstract
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Novel inhibitors of FXIa containing an
(S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to
provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM)
having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model
(ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by
molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal
structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was
achieved by specific modifications derived from careful analysis of the X-ray
crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and
enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90
for thrombus inhibition.
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