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PDBsum entry 4bti
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References listed in PDB file
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Key reference
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Title
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5-Chlorothiophene-2-Carboxylic acid [(s)-2-[2-Methyl-3-(2-Oxopyrrolidin-1-Yl)benzenesulfonylamino]-3-(4-Methylpiperazin-1-Yl)-3-Oxopropyl]amide (sar107375), A selective and potent orally active dual thrombin and factor xa inhibitor.
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Authors
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J.Meneyrol,
M.Follmann,
G.Lassalle,
V.Wehner,
G.Barre,
T.Rousseaux,
J.M.Altenburger,
F.Petit,
Z.Bocskei,
H.Schreuder,
N.Alet,
J.P.Herault,
L.Millet,
F.Dol,
P.Florian,
P.Schaeffer,
F.Sadoun,
S.Klieber,
C.Briot,
F.Bono,
J.M.Herbert.
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Ref.
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J Med Chem, 2013,
56,
9441-9456.
[DOI no: ]
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PubMed id
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Abstract
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Compound 15 (SAR107375), a novel potent dual thrombin and factor Xa inhibitor
resulted from a rational optimization process. Starting from compound 14, with
low factor Xa and modest anti-thrombin inhibitory activities (IC50's of 3.5 and
0.39 μM, respectively), both activities were considerably improved, notably
through the incorporation of a neutral chlorothiophene P1 fragment and tuning of
P2 and P3-P4 fragments. Final optimization of metabolic stability with
microsomes led to the identification of 15, which displays strong activity in
vitro vs factor Xa and thrombin (with Ki's of 1 and 8 nM, respectively). In
addition 15 presents good selectivity versus related serine proteases (roughly
300-fold), including trypsin (1000-fold), and is very active (0.39 μM) in the
thrombin generation time (TGT) coagulation assay in human platelet rich plasma
(PRP). Potent in vivo activity in a rat model of venous thrombosis following iv
and, more importantly, po administration was also observed (ED50 of 0.07 and 2.8
mg/kg, respectively). Bleeding liability was reduced in the rat wire coil model,
more relevant to arterial thrombosis, with 15 (blood loss increase of 2-fold
relative to the ED80 value) compared to rivaroxaban 2 and dabigatran etexilate
1a.
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