Synthesis and Diuretic Activity of Alkyl- and Arylguanidine Analogs of N,N'-Dicyclohexyl-4-morpholinecarboxamidine in Rats and Dogs
Random screening identified N,N'-dicyclohexyl-4-morpholinecarboxamidine (U-18177, 1) as an orally effective nonkaliuretic diuretic in rats. The diuretic profile of 1 and its 1-adamantyl analog (U-37883A, 4) was confirmed orally in dogs, when they were less potent than standard diuretics but sho...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 1994-10, Vol.37 (22), p.3693-3700 |
|---|---|
| Hauptverfasser: | , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3700 |
|---|---|
| container_issue | 22 |
| container_start_page | 3693 |
| container_title | Journal of medicinal chemistry |
| container_volume | 37 |
| creator | Perricone, Sam C Humphrey, Stephen J Skaletzky, Louis L Graham, Boyd E Zandt, Ralph A Zins, Gerald R |
| description | Random screening identified N,N'-dicyclohexyl-4-morpholinecarboxamidine (U-18177, 1) as an orally effective nonkaliuretic diuretic in rats. The diuretic profile of 1 and its 1-adamantyl analog (U-37883A, 4) was confirmed orally in dogs, when they were less potent than standard diuretics but showed furosemide-like natriuresis at > or = 100 mumol/kg. However, acute 1 at 61 and 90 mumol/kg iv resulted in lethal cardiac toxicity in dogs. Many analogs of 1 exhibited qualitatively similar diuretic profiles, but none was sufficiently safe to warrant development. Compound 1 also reversed minoxidil's vasodilation in dogs, which led to vascular interaction studies suggesting that analog 4 may block ATP-sensitive K channels. This K channel-blocking mechanism may contribute to the diuretic activity of the series. This is the first report broadly characterizing the diuretic activity of 1 and representative guanidine analogs in rats and dogs and its toxicity and minoxidil-blocking effects in dogs. |
| doi_str_mv | 10.1021/jm00048a005 |
| format | Article |
| fullrecord | <record><control><sourceid>istex_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1021_jm00048a005</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>ark_67375_TPS_RZ35W5LH_Q</sourcerecordid><originalsourceid>FETCH-LOGICAL-a335t-eb5f08317f6330ca7596e3f5548fdfa2f841ddc78e0d8f4ae6212dadc080d44f3</originalsourceid><addsrcrecordid>eNpt0LtP40AQBvDViRMEuIoayR0F7N3sy3ZKKxwPKeJ4ColmtdkH2eBHtOuc4pp_HIMjREE1xfebGelD6IDAbwKU_FlUAMBzBSB-oBERFDDPgW-hEQClmKaU7aDdGBc9Y4SybbSdjdOU0PEIvd51dTu30cdE1SY59atgW6-TQrf-v2-7pHFJUb50Jf7Ii9CVzytVe-NrmxS1Kpvn-G6uTq6O8KnXnS6buV33nuOqCct5U_ZSqzBr1qoa1nyd3Kp287Df30c_nSqj_bWZe-jh7O_95AJP_51fToopVoyJFtuZcJAzkrmUMdAqE-PUMicEz51xirqcE2N0llswuePKppRQo4yGHAznju2h4-GuDk2MwTq5DL5SoZME5HuT8kuTvT4c9HI1q6z5tJvq-hwPuY-tXX_GKrzINGOZkPfXd_L2iYlHMb2QN70_GrzSUS6aVejLi99-fgMDSIuB</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Synthesis and Diuretic Activity of Alkyl- and Arylguanidine Analogs of N,N'-Dicyclohexyl-4-morpholinecarboxamidine in Rats and Dogs</title><source>MEDLINE</source><source>American Chemical Society Publications</source><creator>Perricone, Sam C ; Humphrey, Stephen J ; Skaletzky, Louis L ; Graham, Boyd E ; Zandt, Ralph A ; Zins, Gerald R</creator><creatorcontrib>Perricone, Sam C ; Humphrey, Stephen J ; Skaletzky, Louis L ; Graham, Boyd E ; Zandt, Ralph A ; Zins, Gerald R</creatorcontrib><description>Random screening identified N,N'-dicyclohexyl-4-morpholinecarboxamidine (U-18177, 1) as an orally effective nonkaliuretic diuretic in rats. The diuretic profile of 1 and its 1-adamantyl analog (U-37883A, 4) was confirmed orally in dogs, when they were less potent than standard diuretics but showed furosemide-like natriuresis at > or = 100 mumol/kg. However, acute 1 at 61 and 90 mumol/kg iv resulted in lethal cardiac toxicity in dogs. Many analogs of 1 exhibited qualitatively similar diuretic profiles, but none was sufficiently safe to warrant development. Compound 1 also reversed minoxidil's vasodilation in dogs, which led to vascular interaction studies suggesting that analog 4 may block ATP-sensitive K channels. This K channel-blocking mechanism may contribute to the diuretic activity of the series. This is the first report broadly characterizing the diuretic activity of 1 and representative guanidine analogs in rats and dogs and its toxicity and minoxidil-blocking effects in dogs.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00048a005</identifier><identifier>PMID: 7966129</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Adamantane - analogs & derivatives ; Adamantane - pharmacology ; Administration, Oral ; Animals ; Blood Pressure - drug effects ; Diuretics - chemical synthesis ; Diuretics - pharmacology ; Dogs ; Drug Interactions ; Female ; Heart Rate - drug effects ; Male ; Minoxidil - pharmacology ; Morpholines - chemical synthesis ; Morpholines - pharmacology ; Potassium Channels - drug effects ; Rats ; Rats, Sprague-Dawley</subject><ispartof>Journal of medicinal chemistry, 1994-10, Vol.37 (22), p.3693-3700</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a335t-eb5f08317f6330ca7596e3f5548fdfa2f841ddc78e0d8f4ae6212dadc080d44f3</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/jm00048a005$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00048a005$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7966129$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Perricone, Sam C</creatorcontrib><creatorcontrib>Humphrey, Stephen J</creatorcontrib><creatorcontrib>Skaletzky, Louis L</creatorcontrib><creatorcontrib>Graham, Boyd E</creatorcontrib><creatorcontrib>Zandt, Ralph A</creatorcontrib><creatorcontrib>Zins, Gerald R</creatorcontrib><title>Synthesis and Diuretic Activity of Alkyl- and Arylguanidine Analogs of N,N'-Dicyclohexyl-4-morpholinecarboxamidine in Rats and Dogs</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Random screening identified N,N'-dicyclohexyl-4-morpholinecarboxamidine (U-18177, 1) as an orally effective nonkaliuretic diuretic in rats. The diuretic profile of 1 and its 1-adamantyl analog (U-37883A, 4) was confirmed orally in dogs, when they were less potent than standard diuretics but showed furosemide-like natriuresis at > or = 100 mumol/kg. However, acute 1 at 61 and 90 mumol/kg iv resulted in lethal cardiac toxicity in dogs. Many analogs of 1 exhibited qualitatively similar diuretic profiles, but none was sufficiently safe to warrant development. Compound 1 also reversed minoxidil's vasodilation in dogs, which led to vascular interaction studies suggesting that analog 4 may block ATP-sensitive K channels. This K channel-blocking mechanism may contribute to the diuretic activity of the series. This is the first report broadly characterizing the diuretic activity of 1 and representative guanidine analogs in rats and dogs and its toxicity and minoxidil-blocking effects in dogs.</description><subject>Adamantane - analogs & derivatives</subject><subject>Adamantane - pharmacology</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>Blood Pressure - drug effects</subject><subject>Diuretics - chemical synthesis</subject><subject>Diuretics - pharmacology</subject><subject>Dogs</subject><subject>Drug Interactions</subject><subject>Female</subject><subject>Heart Rate - drug effects</subject><subject>Male</subject><subject>Minoxidil - pharmacology</subject><subject>Morpholines - chemical synthesis</subject><subject>Morpholines - pharmacology</subject><subject>Potassium Channels - drug effects</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0LtP40AQBvDViRMEuIoayR0F7N3sy3ZKKxwPKeJ4ColmtdkH2eBHtOuc4pp_HIMjREE1xfebGelD6IDAbwKU_FlUAMBzBSB-oBERFDDPgW-hEQClmKaU7aDdGBc9Y4SybbSdjdOU0PEIvd51dTu30cdE1SY59atgW6-TQrf-v2-7pHFJUb50Jf7Ii9CVzytVe-NrmxS1Kpvn-G6uTq6O8KnXnS6buV33nuOqCct5U_ZSqzBr1qoa1nyd3Kp287Df30c_nSqj_bWZe-jh7O_95AJP_51fToopVoyJFtuZcJAzkrmUMdAqE-PUMicEz51xirqcE2N0llswuePKppRQo4yGHAznju2h4-GuDk2MwTq5DL5SoZME5HuT8kuTvT4c9HI1q6z5tJvq-hwPuY-tXX_GKrzINGOZkPfXd_L2iYlHMb2QN70_GrzSUS6aVejLi99-fgMDSIuB</recordid><startdate>19941001</startdate><enddate>19941001</enddate><creator>Perricone, Sam C</creator><creator>Humphrey, Stephen J</creator><creator>Skaletzky, Louis L</creator><creator>Graham, Boyd E</creator><creator>Zandt, Ralph A</creator><creator>Zins, Gerald R</creator><general>American Chemical Society</general><scope>BSCLL</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>19941001</creationdate><title>Synthesis and Diuretic Activity of Alkyl- and Arylguanidine Analogs of N,N'-Dicyclohexyl-4-morpholinecarboxamidine in Rats and Dogs</title><author>Perricone, Sam C ; Humphrey, Stephen J ; Skaletzky, Louis L ; Graham, Boyd E ; Zandt, Ralph A ; Zins, Gerald R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a335t-eb5f08317f6330ca7596e3f5548fdfa2f841ddc78e0d8f4ae6212dadc080d44f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>Adamantane - analogs & derivatives</topic><topic>Adamantane - pharmacology</topic><topic>Administration, Oral</topic><topic>Animals</topic><topic>Blood Pressure - drug effects</topic><topic>Diuretics - chemical synthesis</topic><topic>Diuretics - pharmacology</topic><topic>Dogs</topic><topic>Drug Interactions</topic><topic>Female</topic><topic>Heart Rate - drug effects</topic><topic>Male</topic><topic>Minoxidil - pharmacology</topic><topic>Morpholines - chemical synthesis</topic><topic>Morpholines - pharmacology</topic><topic>Potassium Channels - drug effects</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Perricone, Sam C</creatorcontrib><creatorcontrib>Humphrey, Stephen J</creatorcontrib><creatorcontrib>Skaletzky, Louis L</creatorcontrib><creatorcontrib>Graham, Boyd E</creatorcontrib><creatorcontrib>Zandt, Ralph A</creatorcontrib><creatorcontrib>Zins, Gerald R</creatorcontrib><collection>Istex</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>Perricone, Sam C</au><au>Humphrey, Stephen J</au><au>Skaletzky, Louis L</au><au>Graham, Boyd E</au><au>Zandt, Ralph A</au><au>Zins, Gerald R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Diuretic Activity of Alkyl- and Arylguanidine Analogs of N,N'-Dicyclohexyl-4-morpholinecarboxamidine in Rats and Dogs</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1994-10-01</date><risdate>1994</risdate><volume>37</volume><issue>22</issue><spage>3693</spage><epage>3700</epage><pages>3693-3700</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Random screening identified N,N'-dicyclohexyl-4-morpholinecarboxamidine (U-18177, 1) as an orally effective nonkaliuretic diuretic in rats. The diuretic profile of 1 and its 1-adamantyl analog (U-37883A, 4) was confirmed orally in dogs, when they were less potent than standard diuretics but showed furosemide-like natriuresis at > or = 100 mumol/kg. However, acute 1 at 61 and 90 mumol/kg iv resulted in lethal cardiac toxicity in dogs. Many analogs of 1 exhibited qualitatively similar diuretic profiles, but none was sufficiently safe to warrant development. Compound 1 also reversed minoxidil's vasodilation in dogs, which led to vascular interaction studies suggesting that analog 4 may block ATP-sensitive K channels. This K channel-blocking mechanism may contribute to the diuretic activity of the series. This is the first report broadly characterizing the diuretic activity of 1 and representative guanidine analogs in rats and dogs and its toxicity and minoxidil-blocking effects in dogs.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>7966129</pmid><doi>10.1021/jm00048a005</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1994-10, Vol.37 (22), p.3693-3700 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_crossref_primary_10_1021_jm00048a005 |
| source | MEDLINE; American Chemical Society Publications |
| subjects | Adamantane - analogs & derivatives Adamantane - pharmacology Administration, Oral Animals Blood Pressure - drug effects Diuretics - chemical synthesis Diuretics - pharmacology Dogs Drug Interactions Female Heart Rate - drug effects Male Minoxidil - pharmacology Morpholines - chemical synthesis Morpholines - pharmacology Potassium Channels - drug effects Rats Rats, Sprague-Dawley |
| title | Synthesis and Diuretic Activity of Alkyl- and Arylguanidine Analogs of N,N'-Dicyclohexyl-4-morpholinecarboxamidine in Rats and Dogs |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T08%3A41%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-istex_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Synthesis%20and%20Diuretic%20Activity%20of%20Alkyl-%20and%20Arylguanidine%20Analogs%20of%20N,N'-Dicyclohexyl-4-morpholinecarboxamidine%20in%20Rats%20and%20Dogs&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Perricone,%20Sam%20C&rft.date=1994-10-01&rft.volume=37&rft.issue=22&rft.spage=3693&rft.epage=3700&rft.pages=3693-3700&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/jm00048a005&rft_dat=%3Cistex_cross%3Eark_67375_TPS_RZ35W5LH_Q%3C/istex_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/7966129&rfr_iscdi=true |