Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates
Soluble adenylyl cyclase (sAC: ADCY10) is an enzyme involved in intracellular signaling. Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acros...
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| Veröffentlicht in: | Journal of medicinal chemistry 2022-11, Vol.65 (22), p.15208-15226 |
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| container_title | Journal of medicinal chemistry |
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| creator | Miller, Michael Rossetti, Thomas Ferreira, Jacob Ghanem, Lubna Balbach, Melanie Kaur, Navpreet Levin, Lonny R. Buck, Jochen Kehr, Maria Coquille, Sandrine van den Heuvel, Joop Steegborn, Clemens Fushimi, Makoto Finkin-Groner, Efrat Myers, Robert W. Kargman, Stacia Liverton, Nigel J. Huggins, David J. Meinke, Peter T. |
| description | Soluble adenylyl cyclase (sAC: ADCY10) is an enzyme involved in intracellular signaling. Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acrosome reaction, two processes central to oocyte fertilization. Pharmacologic evaluation of existing sAC inhibitors for utility as on-demand, nonhormonal male contraceptives suggested that both high intrinsic potency, fast on and slow dissociation rates are essential design elements for successful male contraceptive applications. During the course of the medicinal chemistry campaign described here, we identified sAC inhibitors that fulfill these criteria and are suitable for in vivo evaluation of diverse sAC pharmacology. |
| doi_str_mv | 10.1021/acs.jmedchem.2c01133 |
| format | Article |
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Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acrosome reaction, two processes central to oocyte fertilization. Pharmacologic evaluation of existing sAC inhibitors for utility as on-demand, nonhormonal male contraceptives suggested that both high intrinsic potency, fast on and slow dissociation rates are essential design elements for successful male contraceptive applications. During the course of the medicinal chemistry campaign described here, we identified sAC inhibitors that fulfill these criteria and are suitable for in vivo evaluation of diverse sAC pharmacology.</description><identifier>ISSN: 0022-2623</identifier><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.2c01133</identifier><identifier>PMID: 36346696</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Adenylyl Cyclases - drug effects ; Adenylyl Cyclases - metabolism ; Animals ; Contraceptive Agents, Male - chemistry ; Contraceptive Agents, Male - pharmacology ; Male ; Oocytes - metabolism ; Signal Transduction - physiology ; Sperm Motility - drug effects</subject><ispartof>Journal of medicinal chemistry, 2022-11, Vol.65 (22), p.15208-15226</ispartof><rights>2022 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-c93296d457d0ba3171694ec52352aa8a8ee25c6166094fe122c6a00a1ac698c63</citedby><cites>FETCH-LOGICAL-a449t-c93296d457d0ba3171694ec52352aa8a8ee25c6166094fe122c6a00a1ac698c63</cites><orcidid>0000-0003-1579-2496 ; 0000-0001-6168-3659 ; 0000-0002-5204-6356 ; 0000-0003-2599-1050 ; 0000-0002-0913-1467</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.2c01133$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01133$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2751,27055,27903,27904,56717,56767</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36346696$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miller, Michael</creatorcontrib><creatorcontrib>Rossetti, Thomas</creatorcontrib><creatorcontrib>Ferreira, Jacob</creatorcontrib><creatorcontrib>Ghanem, Lubna</creatorcontrib><creatorcontrib>Balbach, Melanie</creatorcontrib><creatorcontrib>Kaur, Navpreet</creatorcontrib><creatorcontrib>Levin, Lonny R.</creatorcontrib><creatorcontrib>Buck, Jochen</creatorcontrib><creatorcontrib>Kehr, Maria</creatorcontrib><creatorcontrib>Coquille, Sandrine</creatorcontrib><creatorcontrib>van den Heuvel, Joop</creatorcontrib><creatorcontrib>Steegborn, Clemens</creatorcontrib><creatorcontrib>Fushimi, Makoto</creatorcontrib><creatorcontrib>Finkin-Groner, Efrat</creatorcontrib><creatorcontrib>Myers, Robert W.</creatorcontrib><creatorcontrib>Kargman, Stacia</creatorcontrib><creatorcontrib>Liverton, Nigel J.</creatorcontrib><creatorcontrib>Huggins, David J.</creatorcontrib><creatorcontrib>Meinke, Peter T.</creatorcontrib><title>Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Soluble adenylyl cyclase (sAC: ADCY10) is an enzyme involved in intracellular signaling. Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acrosome reaction, two processes central to oocyte fertilization. Pharmacologic evaluation of existing sAC inhibitors for utility as on-demand, nonhormonal male contraceptives suggested that both high intrinsic potency, fast on and slow dissociation rates are essential design elements for successful male contraceptive applications. During the course of the medicinal chemistry campaign described here, we identified sAC inhibitors that fulfill these criteria and are suitable for in vivo evaluation of diverse sAC pharmacology.</description><subject>Adenylyl Cyclases - drug effects</subject><subject>Adenylyl Cyclases - metabolism</subject><subject>Animals</subject><subject>Contraceptive Agents, Male - chemistry</subject><subject>Contraceptive Agents, Male - pharmacology</subject><subject>Male</subject><subject>Oocytes - metabolism</subject><subject>Signal Transduction - physiology</subject><subject>Sperm Motility - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kV1v0zAUhiMEYmXwDxDy5ZCa4q-4yQ1SlY4xaRKIwgVX1qlz2nhy7c1ONuWH8H_JSDfBDVe27Pd9bJ0ny94yumCUsw9g0uL6gI1p8bDghjImxLNsxgpOc1lS-TybUcp5zhUXJ9mrlK4ppYJx8TI7EUpIpSo1y36tMdm9n5PN4Lt23Kc5Ad-Qry3EA5jgwt4acOT8DlwPnQ2ehB3ZoAm-yS_QY5wON8H1W4dk1aAf3OBIPRgHCclZWtVzslrXPxl9Ty59a7e2CzGRe9u1ZOPCPVnblIKxE-gbdJheZy924BK-Oa6n2Y9P59_rz_nVl4vLenWVg5RVl5tK8Eo1slg2dAuCLZmqJJqCi4IDlFAi8sIophSt5A4Z50YBpcDAqKo0SpxmHyfuTb99GCX6LoLTN9EeIA46gNX_3njb6n2401WplFDLEXB2BMRw22Pq9MEmg86Bx9AnzZdCMlVKzsaonKImhpQi7p6eYVQ_GNWjUf1oVB-NjrV3f3_xqfSocAzQKfCnHvrox4n9n_kbUMCyAA</recordid><startdate>20221124</startdate><enddate>20221124</enddate><creator>Miller, Michael</creator><creator>Rossetti, Thomas</creator><creator>Ferreira, Jacob</creator><creator>Ghanem, Lubna</creator><creator>Balbach, Melanie</creator><creator>Kaur, Navpreet</creator><creator>Levin, Lonny R.</creator><creator>Buck, Jochen</creator><creator>Kehr, Maria</creator><creator>Coquille, Sandrine</creator><creator>van den Heuvel, Joop</creator><creator>Steegborn, Clemens</creator><creator>Fushimi, Makoto</creator><creator>Finkin-Groner, Efrat</creator><creator>Myers, Robert W.</creator><creator>Kargman, Stacia</creator><creator>Liverton, Nigel J.</creator><creator>Huggins, David J.</creator><creator>Meinke, Peter T.</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>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1579-2496</orcidid><orcidid>https://orcid.org/0000-0001-6168-3659</orcidid><orcidid>https://orcid.org/0000-0002-5204-6356</orcidid><orcidid>https://orcid.org/0000-0003-2599-1050</orcidid><orcidid>https://orcid.org/0000-0002-0913-1467</orcidid></search><sort><creationdate>20221124</creationdate><title>Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates</title><author>Miller, Michael ; Rossetti, Thomas ; Ferreira, Jacob ; Ghanem, Lubna ; Balbach, Melanie ; Kaur, Navpreet ; Levin, Lonny R. ; Buck, Jochen ; Kehr, Maria ; Coquille, Sandrine ; van den Heuvel, Joop ; Steegborn, Clemens ; Fushimi, Makoto ; Finkin-Groner, Efrat ; Myers, Robert W. ; Kargman, Stacia ; Liverton, Nigel J. ; Huggins, David J. ; Meinke, Peter T.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-c93296d457d0ba3171694ec52352aa8a8ee25c6166094fe122c6a00a1ac698c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adenylyl Cyclases - drug effects</topic><topic>Adenylyl Cyclases - metabolism</topic><topic>Animals</topic><topic>Contraceptive Agents, Male - chemistry</topic><topic>Contraceptive Agents, Male - pharmacology</topic><topic>Male</topic><topic>Oocytes - metabolism</topic><topic>Signal Transduction - physiology</topic><topic>Sperm Motility - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Miller, Michael</creatorcontrib><creatorcontrib>Rossetti, Thomas</creatorcontrib><creatorcontrib>Ferreira, Jacob</creatorcontrib><creatorcontrib>Ghanem, Lubna</creatorcontrib><creatorcontrib>Balbach, Melanie</creatorcontrib><creatorcontrib>Kaur, Navpreet</creatorcontrib><creatorcontrib>Levin, Lonny R.</creatorcontrib><creatorcontrib>Buck, Jochen</creatorcontrib><creatorcontrib>Kehr, Maria</creatorcontrib><creatorcontrib>Coquille, Sandrine</creatorcontrib><creatorcontrib>van den Heuvel, Joop</creatorcontrib><creatorcontrib>Steegborn, Clemens</creatorcontrib><creatorcontrib>Fushimi, Makoto</creatorcontrib><creatorcontrib>Finkin-Groner, Efrat</creatorcontrib><creatorcontrib>Myers, Robert W.</creatorcontrib><creatorcontrib>Kargman, Stacia</creatorcontrib><creatorcontrib>Liverton, Nigel J.</creatorcontrib><creatorcontrib>Huggins, David J.</creatorcontrib><creatorcontrib>Meinke, Peter T.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Miller, Michael</au><au>Rossetti, Thomas</au><au>Ferreira, Jacob</au><au>Ghanem, Lubna</au><au>Balbach, Melanie</au><au>Kaur, Navpreet</au><au>Levin, Lonny R.</au><au>Buck, Jochen</au><au>Kehr, Maria</au><au>Coquille, Sandrine</au><au>van den Heuvel, Joop</au><au>Steegborn, Clemens</au><au>Fushimi, Makoto</au><au>Finkin-Groner, Efrat</au><au>Myers, Robert W.</au><au>Kargman, Stacia</au><au>Liverton, Nigel J.</au><au>Huggins, David J.</au><au>Meinke, Peter T.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2022-11-24</date><risdate>2022</risdate><volume>65</volume><issue>22</issue><spage>15208</spage><epage>15226</epage><pages>15208-15226</pages><issn>0022-2623</issn><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>Soluble adenylyl cyclase (sAC: ADCY10) is an enzyme involved in intracellular signaling. Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acrosome reaction, two processes central to oocyte fertilization. Pharmacologic evaluation of existing sAC inhibitors for utility as on-demand, nonhormonal male contraceptives suggested that both high intrinsic potency, fast on and slow dissociation rates are essential design elements for successful male contraceptive applications. During the course of the medicinal chemistry campaign described here, we identified sAC inhibitors that fulfill these criteria and are suitable for in vivo evaluation of diverse sAC pharmacology.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>36346696</pmid><doi>10.1021/acs.jmedchem.2c01133</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0003-1579-2496</orcidid><orcidid>https://orcid.org/0000-0001-6168-3659</orcidid><orcidid>https://orcid.org/0000-0002-5204-6356</orcidid><orcidid>https://orcid.org/0000-0003-2599-1050</orcidid><orcidid>https://orcid.org/0000-0002-0913-1467</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2022-11, Vol.65 (22), p.15208-15226 |
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| subjects | Adenylyl Cyclases - drug effects Adenylyl Cyclases - metabolism Animals Contraceptive Agents, Male - chemistry Contraceptive Agents, Male - pharmacology Male Oocytes - metabolism Signal Transduction - physiology Sperm Motility - drug effects |
| title | Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates |
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