4y8x

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<StructureSection load='4y8x' size='340' side='right' caption='[[4y8x]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
<StructureSection load='4y8x' size='340' side='right' caption='[[4y8x]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4y8x]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y8X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y8X FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4y8x]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y8X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y8X FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4GR:METHYL+(4-{4-CHLORO-2-[(1S)-1-({(2E)-3-[5-CHLORO-2-(1H-TETRAZOL-1-YL)PHENYL]PROP-2-ENOYL}AMINO)-2-PHENYLETHYL]-1H-IMIDAZOL-5-YL}PHENYL)CARBAMATE'>4GR</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4GR:METHYL+(4-{4-CHLORO-2-[(1S)-1-({(2E)-3-[5-CHLORO-2-(1H-TETRAZOL-1-YL)PHENYL]PROP-2-ENOYL}AMINO)-2-PHENYLETHYL]-1H-IMIDAZOL-5-YL}PHENYL)CARBAMATE'>4GR</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4y8y|4y8y]], [[4y8z|4y8z]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4y8y|4y8y]], [[4y8z|4y8z]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">F11 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Coagulation_factor_XIa Coagulation factor XIa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.27 3.4.21.27] </span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Coagulation_factor_XIa Coagulation factor XIa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.27 3.4.21.27] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4y8x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y8x OCA], [http://pdbe.org/4y8x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y8x RCSB], [http://www.ebi.ac.uk/pdbsum/4y8x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4y8x ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4y8x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y8x OCA], [http://pdbe.org/4y8x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y8x RCSB], [http://www.ebi.ac.uk/pdbsum/4y8x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4y8x ProSAT]</span></td></tr>
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<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7nM and modest oral exposure in dogs.
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Structure-activity relationship optimization of phenylalanine P1' and P2' regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2' group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 muM. Dose-dependent efficacy (EC50 of 0.53 muM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.
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Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties.,Pinto DJ, Smallheer JM, Corte JR, Austin EJ, Wang C, Fang T, Smith LM 2nd, Rossi KA, Rendina AR, Bozarth JM, Zhang G, Wei A, Ramamurthy V, Sheriff S, Myers JE Jr, Morin PE, Luettgen JM, Seiffert DA, Quan ML, Wexler RR Bioorg Med Chem Lett. 2015 Feb 4. pii: S0960-894X(15)00040-2. doi:, 10.1016/j.bmcl.2015.01.028. PMID:25728130<ref>PMID:25728130</ref>
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Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)-one as the P2' Moiety.,Hu Z, Wong PC, Gilligan PJ, Han W, Pabbisetty KB, Bozarth JM, Crain EJ, Harper T, Luettgen JM, Myers JE Jr, Ramamurthy V, Rossi KA, Sheriff S, Watson CA, Wei A, Zheng JJ, Seiffert DA, Wexler RR, Quan ML ACS Med Chem Lett. 2015 Apr 8;6(5):590-5. doi: 10.1021/acsmedchemlett.5b00066., eCollection 2015 May 14. PMID:26005539<ref>PMID:26005539</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 4y8x" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 4y8x" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Factor XIa|Factor XIa]]
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Coagulation factor XIa]]
[[Category: Coagulation factor XIa]]
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[[Category: Human]]
[[Category: Sheriff, S]]
[[Category: Sheriff, S]]
[[Category: Blood coagulation factor]]
[[Category: Blood coagulation factor]]

Revision as of 06:15, 18 April 2018

Factor XIa in complex with the inhibitor methyl (4-{4-chloro-2-[(1S)-1-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-2-phenylethyl]-1H-imidazol-5-yl}phenyl)carbamate

4y8x, resolution 1.90Å

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