Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker
A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray c...
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| Veröffentlicht in: | Journal of medicinal chemistry 2017-02, Vol.60 (3), p.1060-1075 |
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| container_title | Journal of medicinal chemistry |
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| creator | Corte, James R Fang, Tianan Osuna, Honey Pinto, Donald J. P Rossi, Karen A Myers, Joseph E Sheriff, Steven Lou, Zhen Zheng, Joanna J Harper, Timothy W Bozarth, Jeffrey M Wu, Yiming Luettgen, Joseph M Seiffert, Dietmar A Decicco, Carl P Wexler, Ruth R Quan, Mimi L |
| description | A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa series, exemplified by compound 16, had a FXIa K i = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x = 0.27 μM) and excellent selectivity against the relevant blood coagulation enzymes. |
| doi_str_mv | 10.1021/acs.jmedchem.6b01460 |
| format | Article |
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P ; Rossi, Karen A ; Myers, Joseph E ; Sheriff, Steven ; Lou, Zhen ; Zheng, Joanna J ; Harper, Timothy W ; Bozarth, Jeffrey M ; Wu, Yiming ; Luettgen, Joseph M ; Seiffert, Dietmar A ; Decicco, Carl P ; Wexler, Ruth R ; Quan, Mimi L</creator><creatorcontrib>Corte, James R ; Fang, Tianan ; Osuna, Honey ; Pinto, Donald J. P ; Rossi, Karen A ; Myers, Joseph E ; Sheriff, Steven ; Lou, Zhen ; Zheng, Joanna J ; Harper, Timothy W ; Bozarth, Jeffrey M ; Wu, Yiming ; Luettgen, Joseph M ; Seiffert, Dietmar A ; Decicco, Carl P ; Wexler, Ruth R ; Quan, Mimi L ; Argonne National Lab. (ANL), Argonne, IL (United States)</creatorcontrib><description>A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa series, exemplified by compound 16, had a FXIa K i = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x = 0.27 μM) and excellent selectivity against the relevant blood coagulation enzymes.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.6b01460</identifier><identifier>PMID: 28085275</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>activated partial thromboplastin time ; amides ; Amides - chemistry ; anticoagulant ; antithrombotic ; aPTT ; Drug Discovery ; factor XIa ; Factor XIa - antagonists & inhibitors ; factor XIa inhibitors ; FXIa ; FXIa inhibitors ; Hydrogen Bonding ; inhibitors ; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY ; Ligands ; macrocycles ; Macrocyclic Compounds - chemistry ; Macrocyclic Compounds - pharmacokinetics ; Macrocyclic Compounds - pharmacology ; Molecular Structure ; peptides and proteins ; phenyls ; Serine Proteinase Inhibitors - chemistry ; Serine Proteinase Inhibitors - pharmacokinetics ; Serine Proteinase Inhibitors - pharmacology ; thrombosis</subject><ispartof>Journal of medicinal chemistry, 2017-02, Vol.60 (3), p.1060-1075</ispartof><rights>Copyright © 2017 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a421t-33977c29a2ae6166be7ff3ec1d3abcad36e3e4be6c2106344bd2416560ea5d6f3</citedby><cites>FETCH-LOGICAL-a421t-33977c29a2ae6166be7ff3ec1d3abcad36e3e4be6c2106344bd2416560ea5d6f3</cites><orcidid>0000-0002-4790-597X ; 000000024790597X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.6b01460$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.6b01460$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28085275$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/servlets/purl/1347764$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Corte, James R</creatorcontrib><creatorcontrib>Fang, Tianan</creatorcontrib><creatorcontrib>Osuna, Honey</creatorcontrib><creatorcontrib>Pinto, Donald J. P</creatorcontrib><creatorcontrib>Rossi, Karen A</creatorcontrib><creatorcontrib>Myers, Joseph E</creatorcontrib><creatorcontrib>Sheriff, Steven</creatorcontrib><creatorcontrib>Lou, Zhen</creatorcontrib><creatorcontrib>Zheng, Joanna J</creatorcontrib><creatorcontrib>Harper, Timothy W</creatorcontrib><creatorcontrib>Bozarth, Jeffrey M</creatorcontrib><creatorcontrib>Wu, Yiming</creatorcontrib><creatorcontrib>Luettgen, Joseph M</creatorcontrib><creatorcontrib>Seiffert, Dietmar A</creatorcontrib><creatorcontrib>Decicco, Carl P</creatorcontrib><creatorcontrib>Wexler, Ruth R</creatorcontrib><creatorcontrib>Quan, Mimi L</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States)</creatorcontrib><title>Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. 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The macrocyclic FXIa series, exemplified by compound 16, had a FXIa K i = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x = 0.27 μM) and excellent selectivity against the relevant blood coagulation enzymes.</description><subject>activated partial thromboplastin time</subject><subject>amides</subject><subject>Amides - chemistry</subject><subject>anticoagulant</subject><subject>antithrombotic</subject><subject>aPTT</subject><subject>Drug Discovery</subject><subject>factor XIa</subject><subject>Factor XIa - antagonists & inhibitors</subject><subject>factor XIa inhibitors</subject><subject>FXIa</subject><subject>FXIa inhibitors</subject><subject>Hydrogen Bonding</subject><subject>inhibitors</subject><subject>INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY</subject><subject>Ligands</subject><subject>macrocycles</subject><subject>Macrocyclic Compounds - chemistry</subject><subject>Macrocyclic Compounds - pharmacokinetics</subject><subject>Macrocyclic Compounds - pharmacology</subject><subject>Molecular Structure</subject><subject>peptides and proteins</subject><subject>phenyls</subject><subject>Serine Proteinase Inhibitors - chemistry</subject><subject>Serine Proteinase Inhibitors - pharmacokinetics</subject><subject>Serine Proteinase Inhibitors - pharmacology</subject><subject>thrombosis</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9P20AQxVdVURNCv0GFrJ64OOw_r01vNGnaSEE9FCRuq_V4TJbGXrq7Rsq374YkSFw4jUbzezN68wj5wuiUUc4uDYTpY4cNrLGbqpoyqegHMmYFp7msqPxIxpRynnPFxYichvBIKRWMi09kxCtaFbwsxqT9E_0AcfCYfzcBm2yOwT70mWuzGwPewRY2FrKFgeh8dr802bJf29qmLnzL5jaAe0a_3fFxjW80151tMFvZ_i_6M3LSmk3Az4c6IXeLH7ezX_nq98_l7HqVG8lZzIW4KkvgV4YbVEypGsu2FQisEaYG0wiFAmWNCjijSkhZN1wyVSiKpmhUKybk636vC9HqADYirMH1PULUTMiyVDJBF3voybt_A4aou-QDNxvToxuCZpVishKCVwmVezTZCsFjq5-87Yzfakb1LgadYtDHGPQhhiQ7P1wY6jR7FR3_ngC6B17kbvB9-sr7O_8DMCCW_A</recordid><startdate>20170209</startdate><enddate>20170209</enddate><creator>Corte, James R</creator><creator>Fang, Tianan</creator><creator>Osuna, Honey</creator><creator>Pinto, Donald J. 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P ; Rossi, Karen A ; Myers, Joseph E ; Sheriff, Steven ; Lou, Zhen ; Zheng, Joanna J ; Harper, Timothy W ; Bozarth, Jeffrey M ; Wu, Yiming ; Luettgen, Joseph M ; Seiffert, Dietmar A ; Decicco, Carl P ; Wexler, Ruth R ; Quan, Mimi L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a421t-33977c29a2ae6166be7ff3ec1d3abcad36e3e4be6c2106344bd2416560ea5d6f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>activated partial thromboplastin time</topic><topic>amides</topic><topic>Amides - chemistry</topic><topic>anticoagulant</topic><topic>antithrombotic</topic><topic>aPTT</topic><topic>Drug Discovery</topic><topic>factor XIa</topic><topic>Factor XIa - antagonists & inhibitors</topic><topic>factor XIa inhibitors</topic><topic>FXIa</topic><topic>FXIa inhibitors</topic><topic>Hydrogen Bonding</topic><topic>inhibitors</topic><topic>INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY</topic><topic>Ligands</topic><topic>macrocycles</topic><topic>Macrocyclic Compounds - chemistry</topic><topic>Macrocyclic Compounds - pharmacokinetics</topic><topic>Macrocyclic Compounds - pharmacology</topic><topic>Molecular Structure</topic><topic>peptides and proteins</topic><topic>phenyls</topic><topic>Serine Proteinase Inhibitors - chemistry</topic><topic>Serine Proteinase Inhibitors - pharmacokinetics</topic><topic>Serine Proteinase Inhibitors - pharmacology</topic><topic>thrombosis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Corte, James R</creatorcontrib><creatorcontrib>Fang, Tianan</creatorcontrib><creatorcontrib>Osuna, Honey</creatorcontrib><creatorcontrib>Pinto, Donald J. 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(ANL), Argonne, IL (United States)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2017-02-09</date><risdate>2017</risdate><volume>60</volume><issue>3</issue><spage>1060</spage><epage>1075</epage><pages>1060-1075</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. 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| source | ACS Publications; MEDLINE |
| subjects | activated partial thromboplastin time amides Amides - chemistry anticoagulant antithrombotic aPTT Drug Discovery factor XIa Factor XIa - antagonists & inhibitors factor XIa inhibitors FXIa FXIa inhibitors Hydrogen Bonding inhibitors INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY Ligands macrocycles Macrocyclic Compounds - chemistry Macrocyclic Compounds - pharmacokinetics Macrocyclic Compounds - pharmacology Molecular Structure peptides and proteins phenyls Serine Proteinase Inhibitors - chemistry Serine Proteinase Inhibitors - pharmacokinetics Serine Proteinase Inhibitors - pharmacology thrombosis |
| title | Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker |
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