Discovery of a biarylamide series of potent, state-dependent NaV1.7 inhibitors
[Display omitted] The NaV1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series of biaryl amides. Optimization led to the identification of several state-dependent, potent and me...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2017-08, Vol.27 (16), p.3817-3824 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 27 |
| creator | Schenkel, Laurie B. DiMauro, Erin F. Nguyen, Hanh N. Chakka, Nagasree Du, Bingfan Foti, Robert S. Guzman-Perez, Angel Jarosh, Michael La, Daniel S. Ligutti, Joseph Milgram, Benjamin C. Moyer, Bryan D. Peterson, Emily A. Roberts, John Yu, Violeta L. Weiss, Matthew M. |
| description | [Display omitted]
The NaV1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series of biaryl amides. Optimization led to the identification of several state-dependent, potent and metabolically stable inhibitors which demonstrated promising levels of selectivity over NaV1.5 and good rat pharmacokinetics. Compound 18, which demonstrated preferential inhibition of a slow inactivated state of NaV1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat NaV1.7 IC50 it failed to demonstrate a robust reduction in nociceptive behavior. |
| doi_str_mv | 10.1016/j.bmcl.2017.06.054 |
| format | Article |
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The NaV1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series of biaryl amides. Optimization led to the identification of several state-dependent, potent and metabolically stable inhibitors which demonstrated promising levels of selectivity over NaV1.5 and good rat pharmacokinetics. Compound 18, which demonstrated preferential inhibition of a slow inactivated state of NaV1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat NaV1.7 IC50 it failed to demonstrate a robust reduction in nociceptive behavior.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2017.06.054</identifier><language>eng</language><publisher>Elsevier Ltd</publisher><subject>NaV1.5 ; NaV1.7 ; Pain ; Sodium channel ; State-dependent</subject><ispartof>Bioorganic & medicinal chemistry letters, 2017-08, Vol.27 (16), p.3817-3824</ispartof><rights>2017 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c314t-9992a11d386410d2341b6d101ee41bb42ab89479a8582aea778b7be30bb2e8843</citedby><cites>FETCH-LOGICAL-c314t-9992a11d386410d2341b6d101ee41bb42ab89479a8582aea778b7be30bb2e8843</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X17306583$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids></links><search><creatorcontrib>Schenkel, Laurie B.</creatorcontrib><creatorcontrib>DiMauro, Erin F.</creatorcontrib><creatorcontrib>Nguyen, Hanh N.</creatorcontrib><creatorcontrib>Chakka, Nagasree</creatorcontrib><creatorcontrib>Du, Bingfan</creatorcontrib><creatorcontrib>Foti, Robert S.</creatorcontrib><creatorcontrib>Guzman-Perez, Angel</creatorcontrib><creatorcontrib>Jarosh, Michael</creatorcontrib><creatorcontrib>La, Daniel S.</creatorcontrib><creatorcontrib>Ligutti, Joseph</creatorcontrib><creatorcontrib>Milgram, Benjamin C.</creatorcontrib><creatorcontrib>Moyer, Bryan D.</creatorcontrib><creatorcontrib>Peterson, Emily A.</creatorcontrib><creatorcontrib>Roberts, John</creatorcontrib><creatorcontrib>Yu, Violeta L.</creatorcontrib><creatorcontrib>Weiss, Matthew M.</creatorcontrib><title>Discovery of a biarylamide series of potent, state-dependent NaV1.7 inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><description>[Display omitted]
The NaV1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series of biaryl amides. Optimization led to the identification of several state-dependent, potent and metabolically stable inhibitors which demonstrated promising levels of selectivity over NaV1.5 and good rat pharmacokinetics. Compound 18, which demonstrated preferential inhibition of a slow inactivated state of NaV1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat NaV1.7 IC50 it failed to demonstrate a robust reduction in nociceptive behavior.</description><subject>NaV1.5</subject><subject>NaV1.7</subject><subject>Pain</subject><subject>Sodium channel</subject><subject>State-dependent</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNp9kE9LxDAQxYMouK5-AU89erA1k6ZpC15k_QvLelHxFpJmFrN0m5rEhf32pqxnTzM83hvm9wi5BFoABXGzKfS26wtGoS6oKGjFj8gMuOB5yWl1TGa0FTRvWv55Ss5C2FAKnHI-I6t7Gzq3Q7_P3DpTmbbK73u1tQazgN5imPTRRRzidRaiipgbHHEwSchW6gOKOrPDl9U2Oh_Oycla9QEv_uacvD8-vC2e8-Xr08vibpl3JfCYt23LFIApG8GBGlZy0MIkEsS0ac6UTr_WrWqqhilUdd3oWmNJtWbYNLyck6vD3dG77x8MUW4TB_a9GtD9BAkt1KWAirJkZQdr510IHtdy9HabKCVQOZUnN3IqT07lSSpkKi-Fbg8hTBA7i16GzuLQobEeuyiNs__FfwEfsHcr</recordid><startdate>20170815</startdate><enddate>20170815</enddate><creator>Schenkel, Laurie B.</creator><creator>DiMauro, Erin F.</creator><creator>Nguyen, Hanh N.</creator><creator>Chakka, Nagasree</creator><creator>Du, Bingfan</creator><creator>Foti, Robert S.</creator><creator>Guzman-Perez, Angel</creator><creator>Jarosh, Michael</creator><creator>La, Daniel S.</creator><creator>Ligutti, Joseph</creator><creator>Milgram, Benjamin C.</creator><creator>Moyer, Bryan D.</creator><creator>Peterson, Emily A.</creator><creator>Roberts, John</creator><creator>Yu, Violeta L.</creator><creator>Weiss, Matthew M.</creator><general>Elsevier Ltd</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20170815</creationdate><title>Discovery of a biarylamide series of potent, state-dependent NaV1.7 inhibitors</title><author>Schenkel, Laurie B. ; DiMauro, Erin F. ; Nguyen, Hanh N. ; Chakka, Nagasree ; Du, Bingfan ; Foti, Robert S. ; Guzman-Perez, Angel ; Jarosh, Michael ; La, Daniel S. ; Ligutti, Joseph ; Milgram, Benjamin C. ; Moyer, Bryan D. ; Peterson, Emily A. ; Roberts, John ; Yu, Violeta L. ; Weiss, Matthew M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c314t-9992a11d386410d2341b6d101ee41bb42ab89479a8582aea778b7be30bb2e8843</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>NaV1.5</topic><topic>NaV1.7</topic><topic>Pain</topic><topic>Sodium channel</topic><topic>State-dependent</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schenkel, Laurie B.</creatorcontrib><creatorcontrib>DiMauro, Erin F.</creatorcontrib><creatorcontrib>Nguyen, Hanh N.</creatorcontrib><creatorcontrib>Chakka, Nagasree</creatorcontrib><creatorcontrib>Du, Bingfan</creatorcontrib><creatorcontrib>Foti, Robert S.</creatorcontrib><creatorcontrib>Guzman-Perez, Angel</creatorcontrib><creatorcontrib>Jarosh, Michael</creatorcontrib><creatorcontrib>La, Daniel S.</creatorcontrib><creatorcontrib>Ligutti, Joseph</creatorcontrib><creatorcontrib>Milgram, Benjamin C.</creatorcontrib><creatorcontrib>Moyer, Bryan D.</creatorcontrib><creatorcontrib>Peterson, Emily A.</creatorcontrib><creatorcontrib>Roberts, John</creatorcontrib><creatorcontrib>Yu, Violeta L.</creatorcontrib><creatorcontrib>Weiss, Matthew M.</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schenkel, Laurie B.</au><au>DiMauro, Erin F.</au><au>Nguyen, Hanh N.</au><au>Chakka, Nagasree</au><au>Du, Bingfan</au><au>Foti, Robert S.</au><au>Guzman-Perez, Angel</au><au>Jarosh, Michael</au><au>La, Daniel S.</au><au>Ligutti, Joseph</au><au>Milgram, Benjamin C.</au><au>Moyer, Bryan D.</au><au>Peterson, Emily A.</au><au>Roberts, John</au><au>Yu, Violeta L.</au><au>Weiss, Matthew M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a biarylamide series of potent, state-dependent NaV1.7 inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><date>2017-08-15</date><risdate>2017</risdate><volume>27</volume><issue>16</issue><spage>3817</spage><epage>3824</epage><pages>3817-3824</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
The NaV1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series of biaryl amides. Optimization led to the identification of several state-dependent, potent and metabolically stable inhibitors which demonstrated promising levels of selectivity over NaV1.5 and good rat pharmacokinetics. Compound 18, which demonstrated preferential inhibition of a slow inactivated state of NaV1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat NaV1.7 IC50 it failed to demonstrate a robust reduction in nociceptive behavior.</abstract><pub>Elsevier Ltd</pub><doi>10.1016/j.bmcl.2017.06.054</doi><tpages>8</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2017-08, Vol.27 (16), p.3817-3824 |
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| language | eng |
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| source | Elsevier ScienceDirect Journals |
| subjects | NaV1.5 NaV1.7 Pain Sodium channel State-dependent |
| title | Discovery of a biarylamide series of potent, state-dependent NaV1.7 inhibitors |
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