Design, Synthesis, and Evaluation of Conformationally Restricted Acetanilides as Potent and Selective β3 Adrenergic Receptor Agonists for the Treatment of Overactive Bladder
A series of conformationally restricted acetanilides were synthesized and evaluated as β3-adrenergic receptor agonists (β3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimiza...
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| Veröffentlicht in: | Journal of medicinal chemistry 2014-02, Vol.57 (4), p.1437-1453 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 57 |
| creator | Moyes, Christopher R Berger, Richard Goble, Stephen D Harper, Bart Shen, Dong-Ming Wang, Liping Bansal, Alka Brown, Patricia N Chen, Airu S Dingley, Karen H Di Salvo, Jerry Fitzmaurice, Aileen Gichuru, Loise N Hurley, Amanda L Jochnowitz, Nina Miller, Randall R Mistry, Shruty Nagabukuro, Hiroshi Salituro, Gino M Sanfiz, Anthony Stevenson, Andra S Villa, Katherine Zamlynny, Beata Struthers, Mary Weber, Ann E Edmondson, Scott D |
| description | A series of conformationally restricted acetanilides were synthesized and evaluated as β3-adrenergic receptor agonists (β3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine β3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent β3-AR mediated responses in a rat bladder hyperactivity model. |
| doi_str_mv | 10.1021/jm4017224 |
| format | Article |
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Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine β3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent β3-AR mediated responses in a rat bladder hyperactivity model.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm4017224</identifier><identifier>PMID: 24437735</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Acetanilides - chemical synthesis ; Acetanilides - pharmacology ; Acetanilides - therapeutic use ; Adrenergic beta-3 Receptor Agonists - chemical synthesis ; Adrenergic beta-3 Receptor Agonists - pharmacology ; Adrenergic beta-3 Receptor Agonists - therapeutic use ; Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Drug Design ; Humans ; Magnetic Resonance Spectroscopy ; Molecular Conformation ; Urinary Bladder, Overactive - drug therapy</subject><ispartof>Journal of medicinal chemistry, 2014-02, Vol.57 (4), p.1437-1453</ispartof><rights>Copyright © 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm4017224$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm4017224$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,27081,27929,27930,56743,56793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24437735$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Moyes, Christopher R</creatorcontrib><creatorcontrib>Berger, Richard</creatorcontrib><creatorcontrib>Goble, Stephen D</creatorcontrib><creatorcontrib>Harper, Bart</creatorcontrib><creatorcontrib>Shen, Dong-Ming</creatorcontrib><creatorcontrib>Wang, Liping</creatorcontrib><creatorcontrib>Bansal, Alka</creatorcontrib><creatorcontrib>Brown, Patricia N</creatorcontrib><creatorcontrib>Chen, Airu S</creatorcontrib><creatorcontrib>Dingley, Karen H</creatorcontrib><creatorcontrib>Di Salvo, Jerry</creatorcontrib><creatorcontrib>Fitzmaurice, Aileen</creatorcontrib><creatorcontrib>Gichuru, Loise N</creatorcontrib><creatorcontrib>Hurley, Amanda L</creatorcontrib><creatorcontrib>Jochnowitz, Nina</creatorcontrib><creatorcontrib>Miller, Randall R</creatorcontrib><creatorcontrib>Mistry, Shruty</creatorcontrib><creatorcontrib>Nagabukuro, Hiroshi</creatorcontrib><creatorcontrib>Salituro, Gino M</creatorcontrib><creatorcontrib>Sanfiz, Anthony</creatorcontrib><creatorcontrib>Stevenson, Andra S</creatorcontrib><creatorcontrib>Villa, Katherine</creatorcontrib><creatorcontrib>Zamlynny, Beata</creatorcontrib><creatorcontrib>Struthers, Mary</creatorcontrib><creatorcontrib>Weber, Ann E</creatorcontrib><creatorcontrib>Edmondson, Scott D</creatorcontrib><title>Design, Synthesis, and Evaluation of Conformationally Restricted Acetanilides as Potent and Selective β3 Adrenergic Receptor Agonists for the Treatment of Overactive Bladder</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of conformationally restricted acetanilides were synthesized and evaluated as β3-adrenergic receptor agonists (β3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine β3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent β3-AR mediated responses in a rat bladder hyperactivity model.</description><subject>Acetanilides - chemical synthesis</subject><subject>Acetanilides - pharmacology</subject><subject>Acetanilides - therapeutic use</subject><subject>Adrenergic beta-3 Receptor Agonists - chemical synthesis</subject><subject>Adrenergic beta-3 Receptor Agonists - pharmacology</subject><subject>Adrenergic beta-3 Receptor Agonists - therapeutic use</subject><subject>Animals</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Molecular Conformation</subject><subject>Urinary Bladder, Overactive - drug therapy</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kUluGzEQRQkjhi0Pi1wg4CZAFu6Eo9heKoozAAYceFg32GS1QoFNKiRbgC6VhQ_iM4W2nKxqwK9XqF8IvaXkIyWMflqPglDFmDhAMyoZaURLxBs0I4Sxhs0ZP0YnOa8JIZwyfoSOmRBcKS5n6M8XyG4VLvDdLpRfNc8XWAeLr7baT7q4GHAc8DKGIabxpdbe7_At5JKcKWDxwkDRwXlnIWOd8c9YIJQXyB14MMVtAT89crywCQKklTN13MCmxIQXqxhcLhlXPK778X0CXcZnQF17s4Wk94DPXlsL6QwdDtpnOH-Np-jh69X98ntzffPtx3Jx3WjGWGmUYpQYe6m0GMDOe1CcGKByEHywrZXEqlb0Ul-2srat7VvTUj0nAxfVFd7zU_Rhz92k-Huqx3ajywa81wHilDsqCZeCKSar9N2rdOpHsN0muVGnXffP4yp4vxdok7t1nFK1sBJI9_y77v_v-F-LTYyN</recordid><startdate>20140227</startdate><enddate>20140227</enddate><creator>Moyes, Christopher R</creator><creator>Berger, Richard</creator><creator>Goble, Stephen D</creator><creator>Harper, Bart</creator><creator>Shen, Dong-Ming</creator><creator>Wang, Liping</creator><creator>Bansal, Alka</creator><creator>Brown, Patricia N</creator><creator>Chen, Airu S</creator><creator>Dingley, Karen H</creator><creator>Di Salvo, Jerry</creator><creator>Fitzmaurice, Aileen</creator><creator>Gichuru, Loise N</creator><creator>Hurley, Amanda L</creator><creator>Jochnowitz, Nina</creator><creator>Miller, Randall R</creator><creator>Mistry, Shruty</creator><creator>Nagabukuro, Hiroshi</creator><creator>Salituro, Gino M</creator><creator>Sanfiz, Anthony</creator><creator>Stevenson, Andra S</creator><creator>Villa, Katherine</creator><creator>Zamlynny, Beata</creator><creator>Struthers, Mary</creator><creator>Weber, Ann E</creator><creator>Edmondson, Scott D</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20140227</creationdate><title>Design, Synthesis, and Evaluation of Conformationally Restricted Acetanilides as Potent and Selective β3 Adrenergic Receptor Agonists for the Treatment of Overactive Bladder</title><author>Moyes, Christopher R ; Berger, Richard ; Goble, Stephen D ; Harper, Bart ; Shen, Dong-Ming ; Wang, Liping ; Bansal, Alka ; Brown, Patricia N ; Chen, Airu S ; Dingley, Karen H ; Di Salvo, Jerry ; Fitzmaurice, Aileen ; Gichuru, Loise N ; Hurley, Amanda L ; Jochnowitz, Nina ; Miller, Randall R ; Mistry, Shruty ; Nagabukuro, Hiroshi ; Salituro, Gino M ; Sanfiz, Anthony ; Stevenson, Andra S ; Villa, Katherine ; Zamlynny, Beata ; Struthers, Mary ; Weber, Ann E ; Edmondson, Scott D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a222t-77210cd97a4fed6be730ce15f43fd8d50d784b5a985ce1ddb8c81a60f347353b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Acetanilides - chemical synthesis</topic><topic>Acetanilides - pharmacology</topic><topic>Acetanilides - therapeutic use</topic><topic>Adrenergic beta-3 Receptor Agonists - chemical synthesis</topic><topic>Adrenergic beta-3 Receptor Agonists - pharmacology</topic><topic>Adrenergic beta-3 Receptor Agonists - therapeutic use</topic><topic>Animals</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Drug Design</topic><topic>Humans</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Molecular Conformation</topic><topic>Urinary Bladder, Overactive - drug therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Moyes, Christopher R</creatorcontrib><creatorcontrib>Berger, Richard</creatorcontrib><creatorcontrib>Goble, Stephen D</creatorcontrib><creatorcontrib>Harper, Bart</creatorcontrib><creatorcontrib>Shen, Dong-Ming</creatorcontrib><creatorcontrib>Wang, Liping</creatorcontrib><creatorcontrib>Bansal, Alka</creatorcontrib><creatorcontrib>Brown, Patricia N</creatorcontrib><creatorcontrib>Chen, Airu S</creatorcontrib><creatorcontrib>Dingley, Karen H</creatorcontrib><creatorcontrib>Di Salvo, Jerry</creatorcontrib><creatorcontrib>Fitzmaurice, Aileen</creatorcontrib><creatorcontrib>Gichuru, Loise N</creatorcontrib><creatorcontrib>Hurley, Amanda L</creatorcontrib><creatorcontrib>Jochnowitz, Nina</creatorcontrib><creatorcontrib>Miller, Randall R</creatorcontrib><creatorcontrib>Mistry, Shruty</creatorcontrib><creatorcontrib>Nagabukuro, Hiroshi</creatorcontrib><creatorcontrib>Salituro, Gino M</creatorcontrib><creatorcontrib>Sanfiz, Anthony</creatorcontrib><creatorcontrib>Stevenson, Andra S</creatorcontrib><creatorcontrib>Villa, Katherine</creatorcontrib><creatorcontrib>Zamlynny, Beata</creatorcontrib><creatorcontrib>Struthers, Mary</creatorcontrib><creatorcontrib>Weber, Ann E</creatorcontrib><creatorcontrib>Edmondson, Scott D</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Moyes, Christopher R</au><au>Berger, Richard</au><au>Goble, Stephen D</au><au>Harper, Bart</au><au>Shen, Dong-Ming</au><au>Wang, Liping</au><au>Bansal, Alka</au><au>Brown, Patricia N</au><au>Chen, Airu S</au><au>Dingley, Karen H</au><au>Di Salvo, Jerry</au><au>Fitzmaurice, Aileen</au><au>Gichuru, Loise N</au><au>Hurley, Amanda L</au><au>Jochnowitz, Nina</au><au>Miller, Randall R</au><au>Mistry, Shruty</au><au>Nagabukuro, Hiroshi</au><au>Salituro, Gino M</au><au>Sanfiz, Anthony</au><au>Stevenson, Andra S</au><au>Villa, Katherine</au><au>Zamlynny, Beata</au><au>Struthers, Mary</au><au>Weber, Ann E</au><au>Edmondson, Scott D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis, and Evaluation of Conformationally Restricted Acetanilides as Potent and Selective β3 Adrenergic Receptor Agonists for the Treatment of Overactive Bladder</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2014-02-27</date><risdate>2014</risdate><volume>57</volume><issue>4</issue><spage>1437</spage><epage>1453</epage><pages>1437-1453</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A series of conformationally restricted acetanilides were synthesized and evaluated as β3-adrenergic receptor agonists (β3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine β3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent β3-AR mediated responses in a rat bladder hyperactivity model.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>24437735</pmid><doi>10.1021/jm4017224</doi><tpages>17</tpages></addata></record> |
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| subjects | Acetanilides - chemical synthesis Acetanilides - pharmacology Acetanilides - therapeutic use Adrenergic beta-3 Receptor Agonists - chemical synthesis Adrenergic beta-3 Receptor Agonists - pharmacology Adrenergic beta-3 Receptor Agonists - therapeutic use Animals CHO Cells Cricetinae Cricetulus Drug Design Humans Magnetic Resonance Spectroscopy Molecular Conformation Urinary Bladder, Overactive - drug therapy |
| title | Design, Synthesis, and Evaluation of Conformationally Restricted Acetanilides as Potent and Selective β3 Adrenergic Receptor Agonists for the Treatment of Overactive Bladder |
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