Potent and Selective ET-A Antagonists. 2. Discovery and Evaluation of Potent and Water Soluble N-(6-(2-(Aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide Derivatives
In the preceding article, we outlined the discovery and structure−activity relationship of a potent and selective ETA receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ETA receptor antagonist activity were identified. This study suggested the metabolic pathway...
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| Veröffentlicht in: | Journal of medicinal chemistry 2001-10, Vol.44 (21), p.3369-3377 |
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| container_title | Journal of medicinal chemistry |
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| creator | Morimoto, Hiroshi Ohashi, Noriko Shimadzu, Hideshi Kushiyama, Emi Kawanishi, Hiroyuki Hosaka, Toshihiro Kawase, Yasushi Yasuda, Kosuke Kikkawa, Kohei Yamauchi-Kohno, Rikako Yamada, Koichiro |
| description | In the preceding article, we outlined the discovery and structure−activity relationship of a potent and selective ETA receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ETA receptor antagonist activity were identified. This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ETA receptor (K i for ETA receptor: 0.015 ± 0.004 nM; for ETB receptor: 41 ± 21 nM). |
| doi_str_mv | 10.1021/jm000538f |
| format | Article |
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This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ETA receptor (K i for ETA receptor: 0.015 ± 0.004 nM; for ETB receptor: 41 ± 21 nM).</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm000538f</identifier><identifier>PMID: 11585442</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Biological Availability ; Cell Line ; Dogs ; Drug Evaluation, Preclinical ; Endothelin Receptor Antagonists ; Humans ; In Vitro Techniques ; Microsomes, Liver - metabolism ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - metabolism ; Pyrimidines - pharmacokinetics ; Rats ; Receptor, Endothelin A ; Receptors, Endothelin - metabolism ; Solubility ; Structure-Activity Relationship ; Sulfonamides - chemical synthesis ; Sulfonamides - chemistry ; Sulfonamides - metabolism ; Sulfonamides - pharmacokinetics ; Water</subject><ispartof>Journal of medicinal chemistry, 2001-10, Vol.44 (21), p.3369-3377</ispartof><rights>Copyright © 2001 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a349t-f80611a677de2b0578cb90ee430b082fd109be33aac4dd70768e47e2cbe45ebc3</citedby><cites>FETCH-LOGICAL-a349t-f80611a677de2b0578cb90ee430b082fd109be33aac4dd70768e47e2cbe45ebc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm000538f$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm000538f$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11585442$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Morimoto, Hiroshi</creatorcontrib><creatorcontrib>Ohashi, Noriko</creatorcontrib><creatorcontrib>Shimadzu, Hideshi</creatorcontrib><creatorcontrib>Kushiyama, Emi</creatorcontrib><creatorcontrib>Kawanishi, Hiroyuki</creatorcontrib><creatorcontrib>Hosaka, Toshihiro</creatorcontrib><creatorcontrib>Kawase, Yasushi</creatorcontrib><creatorcontrib>Yasuda, Kosuke</creatorcontrib><creatorcontrib>Kikkawa, Kohei</creatorcontrib><creatorcontrib>Yamauchi-Kohno, Rikako</creatorcontrib><creatorcontrib>Yamada, Koichiro</creatorcontrib><title>Potent and Selective ET-A Antagonists. 2. Discovery and Evaluation of Potent and Water Soluble N-(6-(2-(Aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide Derivatives</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>In the preceding article, we outlined the discovery and structure−activity relationship of a potent and selective ETA receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ETA receptor antagonist activity were identified. This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ETA receptor (K i for ETA receptor: 0.015 ± 0.004 nM; for ETB receptor: 41 ± 21 nM).</description><subject>Animals</subject><subject>Biological Availability</subject><subject>Cell Line</subject><subject>Dogs</subject><subject>Drug Evaluation, Preclinical</subject><subject>Endothelin Receptor Antagonists</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Microsomes, Liver - metabolism</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - metabolism</subject><subject>Pyrimidines - pharmacokinetics</subject><subject>Rats</subject><subject>Receptor, Endothelin A</subject><subject>Receptors, Endothelin - metabolism</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><subject>Sulfonamides - chemical synthesis</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - metabolism</subject><subject>Sulfonamides - pharmacokinetics</subject><subject>Water</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkU1vEzEQhi1ERUPhwB9AvoCSg4O_dr05Rm1KvwQVCeJoeXdnYYOzDrY36v4Y_itOExUOSCONRvPonZl3EHrD6JRRzj6sN5TSTBTNMzRiGadEFlQ-RyNKOSc85-IUvQxhnSDBuHiBThnLikxKPkK_712ELmLT1XgJFqrY7gAvVmSO5100313XhhimmE_xRRsqtwM_PMKLnbG9ia3rsGvwPyrfTASPl872pQX8iYxzMuZkPPeDdQ_DBOKPfSKSbAffbtq67QY7Cb1tXGdSCfgCfLsz-z3CK3TSGBvg9TGfoa-Xi9X5Fbn7_PH6fH5HjJCzSJqC5oyZXKkaeEkzVVTljAJIQUta8KZmdFaCEMZUsq4VVXkBUgGvSpAZlJU4Q-8PulvvfvUQot6kY8Fa04Hrg1aM8xQygZMDWHkXgodGb9MRxg-aUb3_hX76RWLfHkX7cgP1X_JofgLIAUgWw8NT3_ifOldCZXp1v9T0y83tJb_l-irx7w68qYJeu953yZP_DP4Dqruf-A</recordid><startdate>20011011</startdate><enddate>20011011</enddate><creator>Morimoto, Hiroshi</creator><creator>Ohashi, Noriko</creator><creator>Shimadzu, Hideshi</creator><creator>Kushiyama, Emi</creator><creator>Kawanishi, Hiroyuki</creator><creator>Hosaka, Toshihiro</creator><creator>Kawase, Yasushi</creator><creator>Yasuda, Kosuke</creator><creator>Kikkawa, Kohei</creator><creator>Yamauchi-Kohno, Rikako</creator><creator>Yamada, Koichiro</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><scope>7X8</scope></search><sort><creationdate>20011011</creationdate><title>Potent and Selective ET-A Antagonists. 2. Discovery and Evaluation of Potent and Water Soluble N-(6-(2-(Aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide Derivatives</title><author>Morimoto, Hiroshi ; Ohashi, Noriko ; Shimadzu, Hideshi ; Kushiyama, Emi ; Kawanishi, Hiroyuki ; Hosaka, Toshihiro ; Kawase, Yasushi ; Yasuda, Kosuke ; Kikkawa, Kohei ; Yamauchi-Kohno, Rikako ; Yamada, Koichiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a349t-f80611a677de2b0578cb90ee430b082fd109be33aac4dd70768e47e2cbe45ebc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Animals</topic><topic>Biological Availability</topic><topic>Cell Line</topic><topic>Dogs</topic><topic>Drug Evaluation, Preclinical</topic><topic>Endothelin Receptor Antagonists</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Microsomes, Liver - metabolism</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - metabolism</topic><topic>Pyrimidines - pharmacokinetics</topic><topic>Rats</topic><topic>Receptor, Endothelin A</topic><topic>Receptors, Endothelin - metabolism</topic><topic>Solubility</topic><topic>Structure-Activity Relationship</topic><topic>Sulfonamides - chemical synthesis</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - metabolism</topic><topic>Sulfonamides - pharmacokinetics</topic><topic>Water</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Morimoto, Hiroshi</creatorcontrib><creatorcontrib>Ohashi, Noriko</creatorcontrib><creatorcontrib>Shimadzu, Hideshi</creatorcontrib><creatorcontrib>Kushiyama, Emi</creatorcontrib><creatorcontrib>Kawanishi, Hiroyuki</creatorcontrib><creatorcontrib>Hosaka, Toshihiro</creatorcontrib><creatorcontrib>Kawase, Yasushi</creatorcontrib><creatorcontrib>Yasuda, Kosuke</creatorcontrib><creatorcontrib>Kikkawa, Kohei</creatorcontrib><creatorcontrib>Yamauchi-Kohno, Rikako</creatorcontrib><creatorcontrib>Yamada, Koichiro</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><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Morimoto, Hiroshi</au><au>Ohashi, Noriko</au><au>Shimadzu, Hideshi</au><au>Kushiyama, Emi</au><au>Kawanishi, Hiroyuki</au><au>Hosaka, Toshihiro</au><au>Kawase, Yasushi</au><au>Yasuda, Kosuke</au><au>Kikkawa, Kohei</au><au>Yamauchi-Kohno, Rikako</au><au>Yamada, Koichiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Potent and Selective ET-A Antagonists. 2. Discovery and Evaluation of Potent and Water Soluble N-(6-(2-(Aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide Derivatives</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2001-10-11</date><risdate>2001</risdate><volume>44</volume><issue>21</issue><spage>3369</spage><epage>3377</epage><pages>3369-3377</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>In the preceding article, we outlined the discovery and structure−activity relationship of a potent and selective ETA receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ETA receptor antagonist activity were identified. This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ETA receptor (K i for ETA receptor: 0.015 ± 0.004 nM; for ETB receptor: 41 ± 21 nM).</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>11585442</pmid><doi>10.1021/jm000538f</doi><tpages>9</tpages></addata></record> |
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| subjects | Animals Biological Availability Cell Line Dogs Drug Evaluation, Preclinical Endothelin Receptor Antagonists Humans In Vitro Techniques Microsomes, Liver - metabolism Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - metabolism Pyrimidines - pharmacokinetics Rats Receptor, Endothelin A Receptors, Endothelin - metabolism Solubility Structure-Activity Relationship Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - metabolism Sulfonamides - pharmacokinetics Water |
| title | Potent and Selective ET-A Antagonists. 2. Discovery and Evaluation of Potent and Water Soluble N-(6-(2-(Aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide Derivatives |
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