Structure-Activity Studies of 2,3,4,4a,5,9b-Hexahydroindeno[1,2-c]pyridines as Antispermatogenic Agents for Male Contraception
Analogs of (4aRS,5SR,9bRS)-2-ethyl-2,3,4,4a,5,9b-hexahydro-7-meth yl-5-p- tolyl-1H-indeno[1,2-c]pyridine (Sandoz 20-438, 10a; R1 = ethyl, R2 = R3 = methyl, R4 = H) have been synthesized and tested in mice for their ability to reduce testes weight and disrupt spermatogenesis. The activity was strongl...
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| Veröffentlicht in: | Journal of medicinal chemistry 1995-03, Vol.38 (5), p.753-763 |
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| container_title | Journal of medicinal chemistry |
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| creator | Cook, C. Edgar Wani, Mansukh C Jump, Joseph M Lee, Yue-W Fail, Patricia A Anderson, Stephanie A Gu, Yu-Q Petrow, Vladimir |
| description | Analogs of (4aRS,5SR,9bRS)-2-ethyl-2,3,4,4a,5,9b-hexahydro-7-meth yl-5-p- tolyl-1H-indeno[1,2-c]pyridine (Sandoz 20-438, 10a; R1 = ethyl, R2 = R3 = methyl, R4 = H) have been synthesized and tested in mice for their ability to reduce testes weight and disrupt spermatogenesis. The activity was strongly dependent on stereoisomerism and chirality, consistent with a mechanism of action involving interaction with a specific macromolecule. It was affected by changes in the nitrogen substituent and most strikingly by changes in the p-substituent of the 5-aryl ring. A hydrogen, fluorine, hydroxy, or methoxy substituent led to loss of activity, whereas methyl (Sandoz 20-438, 10a), carboxylate (RTI-4587-054, 10k; R1 = ethyl, R2 = methyl, R3 = COOH, R4 = H), ester (RTI-4587-056, 12b; R1 = ethyl, R2 = methyl, R3 = COOMe, R4 = H), formyl (RTI-4587-030, 12i; R1 = ethyl, R2 = methyl, R3 = CHO, R4 = H), or hydroxymethyl (RTI-4587-055, 12g; R1 = ethyl, R2 = methyl, R3 = CH2OH, R4 = H) groups resulted in antispermatogenic compounds. Methyl ester 12b was an effective antifertility agent, without apparent effects on mating, when given orally to male mice at 7-15 mg/kg daily for 35 days. Further evaluation of these compounds as male contraceptive agents and probes for study of spermatogenesis appears warranted. |
| doi_str_mv | 10.1021/jm00005a003 |
| format | Article |
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Edgar ; Wani, Mansukh C ; Jump, Joseph M ; Lee, Yue-W ; Fail, Patricia A ; Anderson, Stephanie A ; Gu, Yu-Q ; Petrow, Vladimir</creator><creatorcontrib>Cook, C. Edgar ; Wani, Mansukh C ; Jump, Joseph M ; Lee, Yue-W ; Fail, Patricia A ; Anderson, Stephanie A ; Gu, Yu-Q ; Petrow, Vladimir</creatorcontrib><description>Analogs of (4aRS,5SR,9bRS)-2-ethyl-2,3,4,4a,5,9b-hexahydro-7-meth yl-5-p- tolyl-1H-indeno[1,2-c]pyridine (Sandoz 20-438, 10a; R1 = ethyl, R2 = R3 = methyl, R4 = H) have been synthesized and tested in mice for their ability to reduce testes weight and disrupt spermatogenesis. The activity was strongly dependent on stereoisomerism and chirality, consistent with a mechanism of action involving interaction with a specific macromolecule. It was affected by changes in the nitrogen substituent and most strikingly by changes in the p-substituent of the 5-aryl ring. A hydrogen, fluorine, hydroxy, or methoxy substituent led to loss of activity, whereas methyl (Sandoz 20-438, 10a), carboxylate (RTI-4587-054, 10k; R1 = ethyl, R2 = methyl, R3 = COOH, R4 = H), ester (RTI-4587-056, 12b; R1 = ethyl, R2 = methyl, R3 = COOMe, R4 = H), formyl (RTI-4587-030, 12i; R1 = ethyl, R2 = methyl, R3 = CHO, R4 = H), or hydroxymethyl (RTI-4587-055, 12g; R1 = ethyl, R2 = methyl, R3 = CH2OH, R4 = H) groups resulted in antispermatogenic compounds. Methyl ester 12b was an effective antifertility agent, without apparent effects on mating, when given orally to male mice at 7-15 mg/kg daily for 35 days. Further evaluation of these compounds as male contraceptive agents and probes for study of spermatogenesis appears warranted.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00005a003</identifier><identifier>PMID: 7877141</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Administration, Oral ; Animals ; Antispermatogenic Agents - chemical synthesis ; Antispermatogenic Agents - pharmacology ; Biological and medical sciences ; Fertility - drug effects ; Genital system. Reproduction ; Injections, Subcutaneous ; Magnetic Resonance Spectroscopy ; Male ; Medical sciences ; Mice ; Organ Size - drug effects ; Pharmacology. Drug treatments ; Pyridines - chemical synthesis ; Pyridines - pharmacology ; Stereoisomerism ; Structure-Activity Relationship ; Testis - drug effects</subject><ispartof>Journal of medicinal chemistry, 1995-03, Vol.38 (5), p.753-763</ispartof><rights>1995 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a383t-259c263a596a538c7717ed46bd0b2903bf728d368ec880013e3026a7d9d126cf3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00005a003$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00005a003$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3613044$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7877141$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cook, C. Edgar</creatorcontrib><creatorcontrib>Wani, Mansukh C</creatorcontrib><creatorcontrib>Jump, Joseph M</creatorcontrib><creatorcontrib>Lee, Yue-W</creatorcontrib><creatorcontrib>Fail, Patricia A</creatorcontrib><creatorcontrib>Anderson, Stephanie A</creatorcontrib><creatorcontrib>Gu, Yu-Q</creatorcontrib><creatorcontrib>Petrow, Vladimir</creatorcontrib><title>Structure-Activity Studies of 2,3,4,4a,5,9b-Hexahydroindeno[1,2-c]pyridines as Antispermatogenic Agents for Male Contraception</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Analogs of (4aRS,5SR,9bRS)-2-ethyl-2,3,4,4a,5,9b-hexahydro-7-meth yl-5-p- tolyl-1H-indeno[1,2-c]pyridine (Sandoz 20-438, 10a; R1 = ethyl, R2 = R3 = methyl, R4 = H) have been synthesized and tested in mice for their ability to reduce testes weight and disrupt spermatogenesis. The activity was strongly dependent on stereoisomerism and chirality, consistent with a mechanism of action involving interaction with a specific macromolecule. It was affected by changes in the nitrogen substituent and most strikingly by changes in the p-substituent of the 5-aryl ring. A hydrogen, fluorine, hydroxy, or methoxy substituent led to loss of activity, whereas methyl (Sandoz 20-438, 10a), carboxylate (RTI-4587-054, 10k; R1 = ethyl, R2 = methyl, R3 = COOH, R4 = H), ester (RTI-4587-056, 12b; R1 = ethyl, R2 = methyl, R3 = COOMe, R4 = H), formyl (RTI-4587-030, 12i; R1 = ethyl, R2 = methyl, R3 = CHO, R4 = H), or hydroxymethyl (RTI-4587-055, 12g; R1 = ethyl, R2 = methyl, R3 = CH2OH, R4 = H) groups resulted in antispermatogenic compounds. Methyl ester 12b was an effective antifertility agent, without apparent effects on mating, when given orally to male mice at 7-15 mg/kg daily for 35 days. Further evaluation of these compounds as male contraceptive agents and probes for study of spermatogenesis appears warranted.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antispermatogenic Agents - chemical synthesis</subject><subject>Antispermatogenic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Fertility - drug effects</subject><subject>Genital system. Reproduction</subject><subject>Injections, Subcutaneous</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Organ Size - drug effects</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - pharmacology</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Testis - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0M-LEzEUB_AgylpXT56FOQh7cKL5MZPMHLvFdZUVla4giIQ3SUZT22RIMrK9-LcbaSkezOUdvp8XHl-EnlLykhJGX212pLwWCOH30IK2jOCmI819tCCEMcwE4w_Ro5Q2RXHK-Bk6k52UtKEL9Hud46zzHC1e6ux-ubyv1nk2zqYqjBWred3UDdRt3Q_42t7Bj72JwXljffhKa4b1t2kfnXG-LECqlj67NNm4gxy-W-90tSwjp2oMsXoPW1utgs8RtJ2yC_4xejDCNtknx3mOPl-9vl1d45sPb96uljcYeMczZm2vmeDQ9gJa3ulyvLSmEYMhA-sJH0bJOsNFZ3XXEUK55YQJkKY3lAk98nP04vCvjiGlaEc1RbeDuFeUqL8lqn9KLPrZQU_zsLPmZI-tlfz5MYekYTtG8NqlE-OCctI0heEDcynbu1MM8acSkstW3X5cqyt52b378kmoy-IvDh50UpswR18q-e-BfwCTw5P3</recordid><startdate>19950301</startdate><enddate>19950301</enddate><creator>Cook, C. Edgar</creator><creator>Wani, Mansukh C</creator><creator>Jump, Joseph M</creator><creator>Lee, Yue-W</creator><creator>Fail, Patricia A</creator><creator>Anderson, Stephanie A</creator><creator>Gu, Yu-Q</creator><creator>Petrow, Vladimir</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>19950301</creationdate><title>Structure-Activity Studies of 2,3,4,4a,5,9b-Hexahydroindeno[1,2-c]pyridines as Antispermatogenic Agents for Male Contraception</title><author>Cook, C. Edgar ; Wani, Mansukh C ; Jump, Joseph M ; Lee, Yue-W ; Fail, Patricia A ; Anderson, Stephanie A ; Gu, Yu-Q ; Petrow, Vladimir</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a383t-259c263a596a538c7717ed46bd0b2903bf728d368ec880013e3026a7d9d126cf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1995</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Antispermatogenic Agents - chemical synthesis</topic><topic>Antispermatogenic Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Fertility - drug effects</topic><topic>Genital system. Reproduction</topic><topic>Injections, Subcutaneous</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Organ Size - drug effects</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - pharmacology</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Testis - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cook, C. Edgar</creatorcontrib><creatorcontrib>Wani, Mansukh C</creatorcontrib><creatorcontrib>Jump, Joseph M</creatorcontrib><creatorcontrib>Lee, Yue-W</creatorcontrib><creatorcontrib>Fail, Patricia A</creatorcontrib><creatorcontrib>Anderson, Stephanie A</creatorcontrib><creatorcontrib>Gu, Yu-Q</creatorcontrib><creatorcontrib>Petrow, Vladimir</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cook, C. Edgar</au><au>Wani, Mansukh C</au><au>Jump, Joseph M</au><au>Lee, Yue-W</au><au>Fail, Patricia A</au><au>Anderson, Stephanie A</au><au>Gu, Yu-Q</au><au>Petrow, Vladimir</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-Activity Studies of 2,3,4,4a,5,9b-Hexahydroindeno[1,2-c]pyridines as Antispermatogenic Agents for Male Contraception</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1995-03-01</date><risdate>1995</risdate><volume>38</volume><issue>5</issue><spage>753</spage><epage>763</epage><pages>753-763</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Analogs of (4aRS,5SR,9bRS)-2-ethyl-2,3,4,4a,5,9b-hexahydro-7-meth yl-5-p- tolyl-1H-indeno[1,2-c]pyridine (Sandoz 20-438, 10a; R1 = ethyl, R2 = R3 = methyl, R4 = H) have been synthesized and tested in mice for their ability to reduce testes weight and disrupt spermatogenesis. The activity was strongly dependent on stereoisomerism and chirality, consistent with a mechanism of action involving interaction with a specific macromolecule. It was affected by changes in the nitrogen substituent and most strikingly by changes in the p-substituent of the 5-aryl ring. A hydrogen, fluorine, hydroxy, or methoxy substituent led to loss of activity, whereas methyl (Sandoz 20-438, 10a), carboxylate (RTI-4587-054, 10k; R1 = ethyl, R2 = methyl, R3 = COOH, R4 = H), ester (RTI-4587-056, 12b; R1 = ethyl, R2 = methyl, R3 = COOMe, R4 = H), formyl (RTI-4587-030, 12i; R1 = ethyl, R2 = methyl, R3 = CHO, R4 = H), or hydroxymethyl (RTI-4587-055, 12g; R1 = ethyl, R2 = methyl, R3 = CH2OH, R4 = H) groups resulted in antispermatogenic compounds. Methyl ester 12b was an effective antifertility agent, without apparent effects on mating, when given orally to male mice at 7-15 mg/kg daily for 35 days. Further evaluation of these compounds as male contraceptive agents and probes for study of spermatogenesis appears warranted.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>7877141</pmid><doi>10.1021/jm00005a003</doi><tpages>11</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1995-03, Vol.38 (5), p.753-763 |
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| subjects | Administration, Oral Animals Antispermatogenic Agents - chemical synthesis Antispermatogenic Agents - pharmacology Biological and medical sciences Fertility - drug effects Genital system. Reproduction Injections, Subcutaneous Magnetic Resonance Spectroscopy Male Medical sciences Mice Organ Size - drug effects Pharmacology. Drug treatments Pyridines - chemical synthesis Pyridines - pharmacology Stereoisomerism Structure-Activity Relationship Testis - drug effects |
| title | Structure-Activity Studies of 2,3,4,4a,5,9b-Hexahydroindeno[1,2-c]pyridines as Antispermatogenic Agents for Male Contraception |
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