View source for 6w50


==FACTOR XIA IN COMPLEX WITH THE INHIBITOR METHYL ((10R,14S)- 14-(4-(3-CHLORO-2,6-DIFLUOROPHENYL)-6-OXO-3,6-DIHYDRO- 1(2H)-PYRIDINYL)-10-METHYL-9-OXO-8,16- DIAZATRICYCLO[13.3.1.0~2,7~]NONADECA-1(19),2,4,6,15,17- HEXAEN-5-YL)CARBAMATE==
<StructureSection load='6w50' size='340' side='right'caption='[[6w50]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W50 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W50 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SWP:methyl+((10R,14S)-14-(4-(3-chloro-2,6-difluorophenyl)-6-oxo-3,6-dihydro-+1(2h)-pyridinyl)-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0~2,7~]nonadeca-+1(19),2,4,6,15,17-hexaen-5-yl)carbamate'>SWP</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6w50 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w50 OCA], [https://pdbe.org/6w50 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w50 RCSB], [https://www.ebi.ac.uk/pdbsum/6w50 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w50 ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound 4 with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance. Further structure-activity relationship (SAR) studies of heterocyclic core modifications to replace the imidazole core as well as various linkers to the P1 group led to the discovery of compound 6f, a potent FXIa inhibitor with selectivity against most of the relevant serine proteases. Compound 6f also demonstrated excellent pharmacokinetics (PK) profile (high oral bioavailability and low clearance) in multiple preclinical species. Compound 6f achieved robust antithrombotic efficacy in a rabbit efficacy model at doses which preserved hemostasis.

Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species.,Yang W, Wang Y, Lai A, Clark CG, Corte JR, Fang T, Gilligan PJ, Jeon Y, Pabbisetty KB, Rampulla RA, Mathur A, Kaspady M, Neithnadka PR, Arumugam A, Raju S, Rossi KA, Myers JE, Sheriff S, Lou Z, Zheng JJ, Chacko SA, Bozarth JM, Wu Y, Crain EJ, Wong PC, Seiffert DA, Luettgen JM, Lam PYS, Wexler RR, Eiwng WR J Med Chem. 2020 May 26. doi: 10.1021/acs.jmedchem.0c00464. PMID:32456431<ref>PMID:32456431</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[Factor XIa 3D structures|Factor XIa 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Sheriff S]]