Discovery and synthesis of (S)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2- (4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 302872), a novel orally active mixed ET(A)/ET(B) receptor antagonist
Structural variation of the endothelin A-selective antagonist (S)-3-methoxy-2-(4,6-dimethoxypyrimidin-2-yloxy)-3, 3-diphenylpropionic acid (LU 135252) led to analogues which retain ET(A) affinity but exhibit substantial ET(B) affinity as well. The most active derivative obtained is (S)-3-[2-(3, 4-di...
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| Veröffentlicht in: | Journal of medicinal chemistry 1999-08, Vol.42 (16), p.3026-3032 |
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| container_title | Journal of medicinal chemistry |
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| creator | Amberg, W Hergenröder, S Hillen, H Jansen, R Kettschau, G Kling, A Klinge, D Raschack, M Riechers, H Unger, L |
| description | Structural variation of the endothelin A-selective antagonist (S)-3-methoxy-2-(4,6-dimethoxypyrimidin-2-yloxy)-3, 3-diphenylpropionic acid (LU 135252) led to analogues which retain ET(A) affinity but exhibit substantial ET(B) affinity as well. The most active derivative obtained is (S)-3-[2-(3, 4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)- 3, 3-diphenylpropionic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via an acid-catalyzed transetherification. It has a K(i) = 2.15 nM for binding to the ET(A) receptor and a K(i) = 4.75 nM for binding to the ET(B) receptor, is orally available, and antagonizes the big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea pigs each time at a dose of 10 mg/kg. |
| doi_str_mv | 10.1021/jm9910425 |
| format | Article |
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The most active derivative obtained is (S)-3-[2-(3, 4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)- 3, 3-diphenylpropionic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via an acid-catalyzed transetherification. It has a K(i) = 2.15 nM for binding to the ET(A) receptor and a K(i) = 4.75 nM for binding to the ET(B) receptor, is orally available, and antagonizes the big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea pigs each time at a dose of 10 mg/kg.</description><identifier>ISSN: 0022-2623</identifier><identifier>DOI: 10.1021/jm9910425</identifier><identifier>PMID: 10447946</identifier><language>eng</language><publisher>United States</publisher><subject>Administration, Oral ; Animals ; Blood Pressure - drug effects ; Bronchoconstriction - drug effects ; CHO Cells ; Cricetinae ; Endothelin Receptor Antagonists ; Guinea Pigs ; Male ; Propionates - administration & dosage ; Propionates - chemical synthesis ; Propionates - chemistry ; Propionates - pharmacology ; Pyrimidines - administration & dosage ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Radioligand Assay ; Rats ; Rats, Sprague-Dawley ; Receptor, Endothelin A ; Receptor, Endothelin B ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1999-08, Vol.42 (16), p.3026-3032</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10447946$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Amberg, W</creatorcontrib><creatorcontrib>Hergenröder, S</creatorcontrib><creatorcontrib>Hillen, H</creatorcontrib><creatorcontrib>Jansen, R</creatorcontrib><creatorcontrib>Kettschau, G</creatorcontrib><creatorcontrib>Kling, A</creatorcontrib><creatorcontrib>Klinge, D</creatorcontrib><creatorcontrib>Raschack, M</creatorcontrib><creatorcontrib>Riechers, H</creatorcontrib><creatorcontrib>Unger, L</creatorcontrib><title>Discovery and synthesis of (S)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2- (4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 302872), a novel orally active mixed ET(A)/ET(B) receptor antagonist</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>Structural variation of the endothelin A-selective antagonist (S)-3-methoxy-2-(4,6-dimethoxypyrimidin-2-yloxy)-3, 3-diphenylpropionic acid (LU 135252) led to analogues which retain ET(A) affinity but exhibit substantial ET(B) affinity as well. The most active derivative obtained is (S)-3-[2-(3, 4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)- 3, 3-diphenylpropionic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via an acid-catalyzed transetherification. It has a K(i) = 2.15 nM for binding to the ET(A) receptor and a K(i) = 4.75 nM for binding to the ET(B) receptor, is orally available, and antagonizes the big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea pigs each time at a dose of 10 mg/kg.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Blood Pressure - drug effects</subject><subject>Bronchoconstriction - drug effects</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Endothelin Receptor Antagonists</subject><subject>Guinea Pigs</subject><subject>Male</subject><subject>Propionates - administration & dosage</subject><subject>Propionates - chemical synthesis</subject><subject>Propionates - chemistry</subject><subject>Propionates - pharmacology</subject><subject>Pyrimidines - administration & dosage</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptor, Endothelin A</subject><subject>Receptor, Endothelin B</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1UMlOwzAU9AFEy3LgB5BPKJFq8JLNRyirVIkD9IRQ9RLb1JWzEKeIfCG_haWWyzw9zbzRvEHonNErRjm73tRSMprw9ABNKeWc8IyLCTr2fkMpFYyLIzQJgiSXSTZFv3fWV-237kcMjcJ-bIa19tbj1uDoNSaCvHMSiVlClK31sG5_xm6tm9HFu-WDcIKjZJbt-dF1Y29rq2wTmNEFSTCZiUDv7rq-7Wzb2ApDZRWOFkssKC9yHs8w4CZEcbjtwbkQqBrst8a1_dEK379FN_F1wNsY97rS3dD2IfIAn8HMD6fo0IDz-mw_T9Dy4f5t_kQWL4_P85sF6RjnAzEKqiKTkBpdlLxKoTI55CUNQAGESWmZKcZSUMaotNRKipICBVOIQmU0Fyfocucb_vjaaj-s6lCgdg4a3W79KpMyZ1IWQXixF27LWqtVF1qBflz9Vy_-AHsSgvo</recordid><startdate>19990812</startdate><enddate>19990812</enddate><creator>Amberg, W</creator><creator>Hergenröder, S</creator><creator>Hillen, H</creator><creator>Jansen, R</creator><creator>Kettschau, G</creator><creator>Kling, A</creator><creator>Klinge, D</creator><creator>Raschack, M</creator><creator>Riechers, H</creator><creator>Unger, L</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>19990812</creationdate><title>Discovery and synthesis of (S)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2- (4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 302872), a novel orally active mixed ET(A)/ET(B) receptor antagonist</title><author>Amberg, W ; 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The most active derivative obtained is (S)-3-[2-(3, 4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)- 3, 3-diphenylpropionic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via an acid-catalyzed transetherification. It has a K(i) = 2.15 nM for binding to the ET(A) receptor and a K(i) = 4.75 nM for binding to the ET(B) receptor, is orally available, and antagonizes the big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea pigs each time at a dose of 10 mg/kg.</abstract><cop>United States</cop><pmid>10447946</pmid><doi>10.1021/jm9910425</doi><tpages>7</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1999-08, Vol.42 (16), p.3026-3032 |
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| language | eng |
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| source | ACS Publications; MEDLINE |
| subjects | Administration, Oral Animals Blood Pressure - drug effects Bronchoconstriction - drug effects CHO Cells Cricetinae Endothelin Receptor Antagonists Guinea Pigs Male Propionates - administration & dosage Propionates - chemical synthesis Propionates - chemistry Propionates - pharmacology Pyrimidines - administration & dosage Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Radioligand Assay Rats Rats, Sprague-Dawley Receptor, Endothelin A Receptor, Endothelin B Stereoisomerism Structure-Activity Relationship |
| title | Discovery and synthesis of (S)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2- (4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 302872), a novel orally active mixed ET(A)/ET(B) receptor antagonist |
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