Discovery of N‑(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro‑1H‑pyrrolo[2,3‑c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor
The development of bromodomain and extraterminal domain (BET) bromodomain inhibitors and their examination in clinical studies, particularly in oncology settings, has garnered substantial recent interest. An effort to generate novel BET bromodomain inhibitors with excellent potency and drug metaboli...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2017-10, Vol.60 (20), p.8369-8384 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 8384 |
|---|---|
| container_issue | 20 |
| container_start_page | 8369 |
| container_title | Journal of medicinal chemistry |
| container_volume | 60 |
| creator | McDaniel, Keith F Wang, Le Soltwedel, Todd Fidanze, Steven D Hasvold, Lisa A Liu, Dachun Mantei, Robert A Pratt, John K Sheppard, George S Bui, Mai H Faivre, Emily J Huang, Xiaoli Li, Leiming Lin, Xiaoyu Wang, Rongqi Warder, Scott E Wilcox, Denise Albert, Daniel H Magoc, Terrance J Rajaraman, Ganesh Park, Chang H Hutchins, Charles W Shen, Jianwei J Edalji, Rohinton P Sun, Chaohong C Martin, Ruth Gao, Wenqing Wong, Shekman Fang, Guowei Elmore, Steven W Shen, Yu Kati, Warren M |
| description | The development of bromodomain and extraterminal domain (BET) bromodomain inhibitors and their examination in clinical studies, particularly in oncology settings, has garnered substantial recent interest. An effort to generate novel BET bromodomain inhibitors with excellent potency and drug metabolism and pharmacokinetics (DMPK) properties was initiated based upon elaboration of a simple pyridone core. Efforts to develop a bidentate interaction with a critical asparagine residue resulted in the incorporation of a pyrrolopyridone core, which improved potency by 9–19-fold. Additional structure–activity relationship (SAR) efforts aimed both at increasing potency and improving pharmacokinetic properties led to the discovery of the clinical candidate 63 (ABBV-075/mivebresib), which demonstrates excellent potency in biochemical and cellular assays, advantageous exposures and half-life both in animal models and in humans, and in vivo efficacy in mouse models of cancer progression and inflammation. |
| doi_str_mv | 10.1021/acs.jmedchem.7b00746 |
| format | Article |
| fullrecord | <record><control><sourceid>acs_osti_</sourceid><recordid>TN_cdi_osti_scitechconnect_1414456</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>a495971105</sourcerecordid><originalsourceid>FETCH-LOGICAL-a375t-64f3e15dfc11010c4a1fc54489feeb430448539374947e9712cee7ff7eb8a8493</originalsourceid><addsrcrecordid>eNp9kc1uEzEUhacIREPhDRCyukqkOPXfzGSWSZPSSoWyKGwQGnk8dzSuPHZkT6LMjlfgFfskdZsWsWJzf3TPdyz5JMlHSmaUMHomVZjddVCrFrpZXhGSi-xVMqIpI1jMiXidjAhhDLOM8ePkXQh3hBBOGX-bHLN5IYqU0dHR0UoH5XbgB-Qa9PX-95-xwGM2FXilG7N13m1asG4_TDDH4wx30LeDwTl2e4ezaY5r3Q61dxGkl7FsBu-dcT_ZlMdN_Yq7rrXFAg9m8mgVW7SQFsLWNM7KTteAxovl8gcmeXr2Re-g8hB0NZkiib65HmyPpK3RjZfGDGixk9rIygBaete52nVS2yfBet972YPvtJUGrQ6H8XJ9O0EX8ZnI_ktc2VZXunf-ffKmkSbAh-d-kny_WN-eX-Lrm89X54trLHme9jgTDQea1o2ilFCihKSNSoWYFw1AJTiJY8oLnotC5FDklCmAvGlyqOZyLgp-kpwefF3odRmU7kG1ylkLqi-poEKkWRSJg0h5F4KHptx43Uk_lJSUj7GXMfbyJfbyOfaIfTpgm20Vb3-hl5yjgBwET7jb-vhF4f-eD4fKwFM</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Discovery of N‑(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro‑1H‑pyrrolo[2,3‑c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>McDaniel, Keith F ; Wang, Le ; Soltwedel, Todd ; Fidanze, Steven D ; Hasvold, Lisa A ; Liu, Dachun ; Mantei, Robert A ; Pratt, John K ; Sheppard, George S ; Bui, Mai H ; Faivre, Emily J ; Huang, Xiaoli ; Li, Leiming ; Lin, Xiaoyu ; Wang, Rongqi ; Warder, Scott E ; Wilcox, Denise ; Albert, Daniel H ; Magoc, Terrance J ; Rajaraman, Ganesh ; Park, Chang H ; Hutchins, Charles W ; Shen, Jianwei J ; Edalji, Rohinton P ; Sun, Chaohong C ; Martin, Ruth ; Gao, Wenqing ; Wong, Shekman ; Fang, Guowei ; Elmore, Steven W ; Shen, Yu ; Kati, Warren M</creator><creatorcontrib>McDaniel, Keith F ; Wang, Le ; Soltwedel, Todd ; Fidanze, Steven D ; Hasvold, Lisa A ; Liu, Dachun ; Mantei, Robert A ; Pratt, John K ; Sheppard, George S ; Bui, Mai H ; Faivre, Emily J ; Huang, Xiaoli ; Li, Leiming ; Lin, Xiaoyu ; Wang, Rongqi ; Warder, Scott E ; Wilcox, Denise ; Albert, Daniel H ; Magoc, Terrance J ; Rajaraman, Ganesh ; Park, Chang H ; Hutchins, Charles W ; Shen, Jianwei J ; Edalji, Rohinton P ; Sun, Chaohong C ; Martin, Ruth ; Gao, Wenqing ; Wong, Shekman ; Fang, Guowei ; Elmore, Steven W ; Shen, Yu ; Kati, Warren M ; Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>The development of bromodomain and extraterminal domain (BET) bromodomain inhibitors and their examination in clinical studies, particularly in oncology settings, has garnered substantial recent interest. An effort to generate novel BET bromodomain inhibitors with excellent potency and drug metabolism and pharmacokinetics (DMPK) properties was initiated based upon elaboration of a simple pyridone core. Efforts to develop a bidentate interaction with a critical asparagine residue resulted in the incorporation of a pyrrolopyridone core, which improved potency by 9–19-fold. Additional structure–activity relationship (SAR) efforts aimed both at increasing potency and improving pharmacokinetic properties led to the discovery of the clinical candidate 63 (ABBV-075/mivebresib), which demonstrates excellent potency in biochemical and cellular assays, advantageous exposures and half-life both in animal models and in humans, and in vivo efficacy in mouse models of cancer progression and inflammation.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.7b00746</identifier><identifier>PMID: 28949521</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Cell Line, Tumor ; Chromatography, High Pressure Liquid ; Drug Discovery ; Fluorescence Resonance Energy Transfer ; Half-Life ; Humans ; Mass Spectrometry ; Mice ; Proteins - antagonists & inhibitors ; Proton Magnetic Resonance Spectroscopy ; Pyridones - chemistry ; Pyridones - pharmacokinetics ; Pyridones - pharmacology ; Structure-Activity Relationship ; Sulfonamides - chemistry ; Sulfonamides - pharmacokinetics ; Sulfonamides - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2017-10, Vol.60 (20), p.8369-8384</ispartof><rights>Copyright © 2017 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a375t-64f3e15dfc11010c4a1fc54489feeb430448539374947e9712cee7ff7eb8a8493</citedby><cites>FETCH-LOGICAL-a375t-64f3e15dfc11010c4a1fc54489feeb430448539374947e9712cee7ff7eb8a8493</cites><orcidid>0000-0003-2611-8480 ; 0000-0001-5704-3288 ; 0000000326118480 ; 0000000157043288</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.7b00746$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00746$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28949521$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1414456$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>McDaniel, Keith F</creatorcontrib><creatorcontrib>Wang, Le</creatorcontrib><creatorcontrib>Soltwedel, Todd</creatorcontrib><creatorcontrib>Fidanze, Steven D</creatorcontrib><creatorcontrib>Hasvold, Lisa A</creatorcontrib><creatorcontrib>Liu, Dachun</creatorcontrib><creatorcontrib>Mantei, Robert A</creatorcontrib><creatorcontrib>Pratt, John K</creatorcontrib><creatorcontrib>Sheppard, George S</creatorcontrib><creatorcontrib>Bui, Mai H</creatorcontrib><creatorcontrib>Faivre, Emily J</creatorcontrib><creatorcontrib>Huang, Xiaoli</creatorcontrib><creatorcontrib>Li, Leiming</creatorcontrib><creatorcontrib>Lin, Xiaoyu</creatorcontrib><creatorcontrib>Wang, Rongqi</creatorcontrib><creatorcontrib>Warder, Scott E</creatorcontrib><creatorcontrib>Wilcox, Denise</creatorcontrib><creatorcontrib>Albert, Daniel H</creatorcontrib><creatorcontrib>Magoc, Terrance J</creatorcontrib><creatorcontrib>Rajaraman, Ganesh</creatorcontrib><creatorcontrib>Park, Chang H</creatorcontrib><creatorcontrib>Hutchins, Charles W</creatorcontrib><creatorcontrib>Shen, Jianwei J</creatorcontrib><creatorcontrib>Edalji, Rohinton P</creatorcontrib><creatorcontrib>Sun, Chaohong C</creatorcontrib><creatorcontrib>Martin, Ruth</creatorcontrib><creatorcontrib>Gao, Wenqing</creatorcontrib><creatorcontrib>Wong, Shekman</creatorcontrib><creatorcontrib>Fang, Guowei</creatorcontrib><creatorcontrib>Elmore, Steven W</creatorcontrib><creatorcontrib>Shen, Yu</creatorcontrib><creatorcontrib>Kati, Warren M</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Discovery of N‑(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro‑1H‑pyrrolo[2,3‑c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The development of bromodomain and extraterminal domain (BET) bromodomain inhibitors and their examination in clinical studies, particularly in oncology settings, has garnered substantial recent interest. An effort to generate novel BET bromodomain inhibitors with excellent potency and drug metabolism and pharmacokinetics (DMPK) properties was initiated based upon elaboration of a simple pyridone core. Efforts to develop a bidentate interaction with a critical asparagine residue resulted in the incorporation of a pyrrolopyridone core, which improved potency by 9–19-fold. Additional structure–activity relationship (SAR) efforts aimed both at increasing potency and improving pharmacokinetic properties led to the discovery of the clinical candidate 63 (ABBV-075/mivebresib), which demonstrates excellent potency in biochemical and cellular assays, advantageous exposures and half-life both in animal models and in humans, and in vivo efficacy in mouse models of cancer progression and inflammation.</description><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Drug Discovery</subject><subject>Fluorescence Resonance Energy Transfer</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Mass Spectrometry</subject><subject>Mice</subject><subject>Proteins - antagonists & inhibitors</subject><subject>Proton Magnetic Resonance Spectroscopy</subject><subject>Pyridones - chemistry</subject><subject>Pyridones - pharmacokinetics</subject><subject>Pyridones - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - pharmacokinetics</subject><subject>Sulfonamides - pharmacology</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>eNp9kc1uEzEUhacIREPhDRCyukqkOPXfzGSWSZPSSoWyKGwQGnk8dzSuPHZkT6LMjlfgFfskdZsWsWJzf3TPdyz5JMlHSmaUMHomVZjddVCrFrpZXhGSi-xVMqIpI1jMiXidjAhhDLOM8ePkXQh3hBBOGX-bHLN5IYqU0dHR0UoH5XbgB-Qa9PX-95-xwGM2FXilG7N13m1asG4_TDDH4wx30LeDwTl2e4ezaY5r3Q61dxGkl7FsBu-dcT_ZlMdN_Yq7rrXFAg9m8mgVW7SQFsLWNM7KTteAxovl8gcmeXr2Re-g8hB0NZkiib65HmyPpK3RjZfGDGixk9rIygBaete52nVS2yfBet972YPvtJUGrQ6H8XJ9O0EX8ZnI_ktc2VZXunf-ffKmkSbAh-d-kny_WN-eX-Lrm89X54trLHme9jgTDQea1o2ilFCihKSNSoWYFw1AJTiJY8oLnotC5FDklCmAvGlyqOZyLgp-kpwefF3odRmU7kG1ylkLqi-poEKkWRSJg0h5F4KHptx43Uk_lJSUj7GXMfbyJfbyOfaIfTpgm20Vb3-hl5yjgBwET7jb-vhF4f-eD4fKwFM</recordid><startdate>20171026</startdate><enddate>20171026</enddate><creator>McDaniel, Keith F</creator><creator>Wang, Le</creator><creator>Soltwedel, Todd</creator><creator>Fidanze, Steven D</creator><creator>Hasvold, Lisa A</creator><creator>Liu, Dachun</creator><creator>Mantei, Robert A</creator><creator>Pratt, John K</creator><creator>Sheppard, George S</creator><creator>Bui, Mai H</creator><creator>Faivre, Emily J</creator><creator>Huang, Xiaoli</creator><creator>Li, Leiming</creator><creator>Lin, Xiaoyu</creator><creator>Wang, Rongqi</creator><creator>Warder, Scott E</creator><creator>Wilcox, Denise</creator><creator>Albert, Daniel H</creator><creator>Magoc, Terrance J</creator><creator>Rajaraman, Ganesh</creator><creator>Park, Chang H</creator><creator>Hutchins, Charles W</creator><creator>Shen, Jianwei J</creator><creator>Edalji, Rohinton P</creator><creator>Sun, Chaohong C</creator><creator>Martin, Ruth</creator><creator>Gao, Wenqing</creator><creator>Wong, Shekman</creator><creator>Fang, Guowei</creator><creator>Elmore, Steven W</creator><creator>Shen, Yu</creator><creator>Kati, Warren M</creator><general>American Chemical Society</general><general>American Chemical Society (ACS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>OTOTI</scope><orcidid>https://orcid.org/0000-0003-2611-8480</orcidid><orcidid>https://orcid.org/0000-0001-5704-3288</orcidid><orcidid>https://orcid.org/0000000326118480</orcidid><orcidid>https://orcid.org/0000000157043288</orcidid></search><sort><creationdate>20171026</creationdate><title>Discovery of N‑(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro‑1H‑pyrrolo[2,3‑c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor</title><author>McDaniel, Keith F ; Wang, Le ; Soltwedel, Todd ; Fidanze, Steven D ; Hasvold, Lisa A ; Liu, Dachun ; Mantei, Robert A ; Pratt, John K ; Sheppard, George S ; Bui, Mai H ; Faivre, Emily J ; Huang, Xiaoli ; Li, Leiming ; Lin, Xiaoyu ; Wang, Rongqi ; Warder, Scott E ; Wilcox, Denise ; Albert, Daniel H ; Magoc, Terrance J ; Rajaraman, Ganesh ; Park, Chang H ; Hutchins, Charles W ; Shen, Jianwei J ; Edalji, Rohinton P ; Sun, Chaohong C ; Martin, Ruth ; Gao, Wenqing ; Wong, Shekman ; Fang, Guowei ; Elmore, Steven W ; Shen, Yu ; Kati, Warren M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a375t-64f3e15dfc11010c4a1fc54489feeb430448539374947e9712cee7ff7eb8a8493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Cell Line, Tumor</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Drug Discovery</topic><topic>Fluorescence Resonance Energy Transfer</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Mass Spectrometry</topic><topic>Mice</topic><topic>Proteins - antagonists & inhibitors</topic><topic>Proton Magnetic Resonance Spectroscopy</topic><topic>Pyridones - chemistry</topic><topic>Pyridones - pharmacokinetics</topic><topic>Pyridones - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - pharmacokinetics</topic><topic>Sulfonamides - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McDaniel, Keith F</creatorcontrib><creatorcontrib>Wang, Le</creatorcontrib><creatorcontrib>Soltwedel, Todd</creatorcontrib><creatorcontrib>Fidanze, Steven D</creatorcontrib><creatorcontrib>Hasvold, Lisa A</creatorcontrib><creatorcontrib>Liu, Dachun</creatorcontrib><creatorcontrib>Mantei, Robert A</creatorcontrib><creatorcontrib>Pratt, John K</creatorcontrib><creatorcontrib>Sheppard, George S</creatorcontrib><creatorcontrib>Bui, Mai H</creatorcontrib><creatorcontrib>Faivre, Emily J</creatorcontrib><creatorcontrib>Huang, Xiaoli</creatorcontrib><creatorcontrib>Li, Leiming</creatorcontrib><creatorcontrib>Lin, Xiaoyu</creatorcontrib><creatorcontrib>Wang, Rongqi</creatorcontrib><creatorcontrib>Warder, Scott E</creatorcontrib><creatorcontrib>Wilcox, Denise</creatorcontrib><creatorcontrib>Albert, Daniel H</creatorcontrib><creatorcontrib>Magoc, Terrance J</creatorcontrib><creatorcontrib>Rajaraman, Ganesh</creatorcontrib><creatorcontrib>Park, Chang H</creatorcontrib><creatorcontrib>Hutchins, Charles W</creatorcontrib><creatorcontrib>Shen, Jianwei J</creatorcontrib><creatorcontrib>Edalji, Rohinton P</creatorcontrib><creatorcontrib>Sun, Chaohong C</creatorcontrib><creatorcontrib>Martin, Ruth</creatorcontrib><creatorcontrib>Gao, Wenqing</creatorcontrib><creatorcontrib>Wong, Shekman</creatorcontrib><creatorcontrib>Fang, Guowei</creatorcontrib><creatorcontrib>Elmore, Steven W</creatorcontrib><creatorcontrib>Shen, Yu</creatorcontrib><creatorcontrib>Kati, Warren M</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>OSTI.GOV</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McDaniel, Keith F</au><au>Wang, Le</au><au>Soltwedel, Todd</au><au>Fidanze, Steven D</au><au>Hasvold, Lisa A</au><au>Liu, Dachun</au><au>Mantei, Robert A</au><au>Pratt, John K</au><au>Sheppard, George S</au><au>Bui, Mai H</au><au>Faivre, Emily J</au><au>Huang, Xiaoli</au><au>Li, Leiming</au><au>Lin, Xiaoyu</au><au>Wang, Rongqi</au><au>Warder, Scott E</au><au>Wilcox, Denise</au><au>Albert, Daniel H</au><au>Magoc, Terrance J</au><au>Rajaraman, Ganesh</au><au>Park, Chang H</au><au>Hutchins, Charles W</au><au>Shen, Jianwei J</au><au>Edalji, Rohinton P</au><au>Sun, Chaohong C</au><au>Martin, Ruth</au><au>Gao, Wenqing</au><au>Wong, Shekman</au><au>Fang, Guowei</au><au>Elmore, Steven W</au><au>Shen, Yu</au><au>Kati, Warren M</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of N‑(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro‑1H‑pyrrolo[2,3‑c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2017-10-26</date><risdate>2017</risdate><volume>60</volume><issue>20</issue><spage>8369</spage><epage>8384</epage><pages>8369-8384</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The development of bromodomain and extraterminal domain (BET) bromodomain inhibitors and their examination in clinical studies, particularly in oncology settings, has garnered substantial recent interest. An effort to generate novel BET bromodomain inhibitors with excellent potency and drug metabolism and pharmacokinetics (DMPK) properties was initiated based upon elaboration of a simple pyridone core. Efforts to develop a bidentate interaction with a critical asparagine residue resulted in the incorporation of a pyrrolopyridone core, which improved potency by 9–19-fold. Additional structure–activity relationship (SAR) efforts aimed both at increasing potency and improving pharmacokinetic properties led to the discovery of the clinical candidate 63 (ABBV-075/mivebresib), which demonstrates excellent potency in biochemical and cellular assays, advantageous exposures and half-life both in animal models and in humans, and in vivo efficacy in mouse models of cancer progression and inflammation.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>28949521</pmid><doi>10.1021/acs.jmedchem.7b00746</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-2611-8480</orcidid><orcidid>https://orcid.org/0000-0001-5704-3288</orcidid><orcidid>https://orcid.org/0000000326118480</orcidid><orcidid>https://orcid.org/0000000157043288</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2017-10, Vol.60 (20), p.8369-8384 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_osti_scitechconnect_1414456 |
| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Cell Line, Tumor Chromatography, High Pressure Liquid Drug Discovery Fluorescence Resonance Energy Transfer Half-Life Humans Mass Spectrometry Mice Proteins - antagonists & inhibitors Proton Magnetic Resonance Spectroscopy Pyridones - chemistry Pyridones - pharmacokinetics Pyridones - pharmacology Structure-Activity Relationship Sulfonamides - chemistry Sulfonamides - pharmacokinetics Sulfonamides - pharmacology |
| title | Discovery of N‑(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro‑1H‑pyrrolo[2,3‑c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T20%3A26%3A18IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-acs_osti_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%20N%E2%80%91(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro%E2%80%911H%E2%80%91pyrrolo%5B2,3%E2%80%91c%5Dpyridin-4-yl)phenyl)ethanesulfonamide%20(ABBV-075/Mivebresib),%20a%20Potent%20and%20Orally%20Available%20Bromodomain%20and%20Extraterminal%20Domain%20(BET)%20Family%20Bromodomain%20Inhibitor&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=McDaniel,%20Keith%20F&rft.aucorp=Argonne%20National%20Lab.%20(ANL),%20Argonne,%20IL%20(United%20States).%20Advanced%20Photon%20Source%20(APS)&rft.date=2017-10-26&rft.volume=60&rft.issue=20&rft.spage=8369&rft.epage=8384&rft.pages=8369-8384&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/acs.jmedchem.7b00746&rft_dat=%3Cacs_osti_%3Ea495971105%3C/acs_osti_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/28949521&rfr_iscdi=true |