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PDBsum entry 5qtt
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Hydrolase/hydrolase inhibitor
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PDB id
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5qtt
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Factor xia in complex with the inhibitor methyl [(3r,7s)-7-{[5-amino- 1-(3-chloro-2-fluorophenyl)-1h-pyrazole-4-carbonyl]amino}-3-methyl-2- oxo-2,3,4,5,6,7-hexahydro-1h-12,8-(metheno)-1,9- benzodiazacyclotetradecin-15-yl]carbamate
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Structure:
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Coagulation factor xi. Chain: a. Fragment: coagulation factor xi, heavy chain. Synonym: fxi,plasma thromboplastin antecedent,pta. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.23Å
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R-factor:
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0.186
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R-free:
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0.226
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Authors:
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S.Sheriff
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Key ref:
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J.R.Corte
et al.
(2020).
Potent, Orally Bioavailable, and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups.
J Med Chem,
63,
784-803.
PubMed id:
DOI:
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Date:
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16-Oct-19
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Release date:
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25-Dec-19
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PROCHECK
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Headers
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References
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P03951
(FA11_HUMAN) -
Coagulation factor XI from Homo sapiens
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Seq:
Struc:
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625 a.a.
238 a.a.*
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Key: |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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Enzyme class:
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E.C.3.4.21.27
- coagulation factor XIa.
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Reaction:
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Selective cleavage of Arg-|-Ala and Arg-|-Val bonds in factor IX to form factor IXa.
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DOI no:
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J Med Chem
63:784-803
(2020)
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PubMed id:
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Potent, Orally Bioavailable, and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups.
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J.R.Corte,
D.J.P.Pinto,
T.Fang,
H.Osuna,
W.Yang,
Y.Wang,
A.Lai,
C.G.Clark,
J.H.Sun,
R.Rampulla,
A.Mathur,
M.Kaspady,
P.R.Neithnadka,
Y.C.Li,
K.A.Rossi,
J.E.Myers,
S.Sheriff,
Z.Lou,
T.W.Harper,
C.Huang,
J.J.Zheng,
J.M.Bozarth,
Y.Wu,
P.C.Wong,
E.J.Crain,
D.A.Seiffert,
J.M.Luettgen,
P.Y.S.Lam,
R.R.Wexler,
W.R.Ewing.
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ABSTRACT
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Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show
excellent efficacy in preclinical thrombosis models with minimal effects on
hemostasis. The discovery of potent and selective FXIa inhibitors which are also
orally bioavailable has been a challenge. Here, we describe optimization of the
imidazole-based macrocyclic series and our initial progress toward meeting this
challenge. A two-pronged strategy, which focused on replacement of the imidazole
scaffold and the design of new P1 groups, led to the discovery of potent, orally
bioavailable pyridine-based macrocyclic FXIa inhibitors. Moreover,
pyridine-based macrocycle 19, possessing the phenylimidazole carboxamide
P1, exhibited excellent selectivity against relevant blood coagulation enzymes
and displayed antithrombotic efficacy in a rabbit thrombosis model.
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Links
