3-(2-Aminocarbonylphenyl)propanoic acid analogs as potent and selective EP3 receptor antagonists. Part 2: Optimization of the side chains to improve in vitro and in vivo potencies
We identified a series of 3-[2-{[(3-methyl-1-phenylbutyl)amino]carbonyl}-4-(phenoxymethyl)phenyl]propanoic acid analogs as potent and selective EP3 receptor antagonists. Introduction of substituents into the two benzene nucleus resulted in the increased in vitro activities. Several compounds exhibit...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2010-02, Vol.18 (4), p.1641-1658 |
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| creator | Asada, Masaki Iwahashi, Maki Obitsu, Tetsuo Kinoshita, Atsushi Nakai, Yoshihiko Onoda, Takahiro Nagase, Toshihiko Tanaka, Motoyuki Yamaura, Yoshiyuki Takizawa, Hiroya Yoshikawa, Ken Sato, Kazutoyo Narita, Masami Ohuchida, Shuichi Nakai, Hisao Toda, Masaaki |
| description | We identified a series of 3-[2-{[(3-methyl-1-phenylbutyl)amino]carbonyl}-4-(phenoxymethyl)phenyl]propanoic acid analogs as potent and selective EP3 receptor antagonists. Introduction of substituents into the two benzene nucleus resulted in the increased in vitro activities. Several compounds exhibited potent inhibitory effect against the PGE2-induced uterine contraction in pregnant rats.
A series of 3-[2-{[(3-methyl-1-phenylbutyl)amino]carbonyl}-4-(phenoxymethyl)phenyl]propanoic acid analogs were synthesized and evaluated for their in vitro potency. In most cases, introduction of one or two substituents into the two phenyl moieties resulted in the tendency of an increase or retention of in vitro activities. Several compounds, which showed excellent subtype selectivity, were evaluated for their inhibitory effect against PGE2-induced uterine contraction in pregnant rats, which is thought to be mediated by the EP3 receptor subtype. The structure–activity relationships (SARs) are also discussed. |
| doi_str_mv | 10.1016/j.bmc.2009.12.068 |
| format | Article |
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A series of 3-[2-{[(3-methyl-1-phenylbutyl)amino]carbonyl}-4-(phenoxymethyl)phenyl]propanoic acid analogs were synthesized and evaluated for their in vitro potency. In most cases, introduction of one or two substituents into the two phenyl moieties resulted in the tendency of an increase or retention of in vitro activities. Several compounds, which showed excellent subtype selectivity, were evaluated for their inhibitory effect against PGE2-induced uterine contraction in pregnant rats, which is thought to be mediated by the EP3 receptor subtype. The structure–activity relationships (SARs) are also discussed.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2009.12.068</identifier><identifier>PMID: 20129791</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Animals ; Antagonist ; Biological and medical sciences ; CHO Cells ; Cricetinae ; Cricetulus ; EP3 receptor ; Female ; Genital system. Reproduction ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Medical sciences ; Pharmacology. Drug treatments ; Pregnancy ; Propionates - chemistry ; Propionates - pharmacokinetics ; Propionates - pharmacology ; Rats ; Receptors, Prostaglandin E - antagonists & inhibitors ; Receptors, Prostaglandin E, EP3 Subtype ; Uterine contraction ; Uterine Contraction - drug effects</subject><ispartof>Bioorganic & medicinal chemistry, 2010-02, Vol.18 (4), p.1641-1658</ispartof><rights>2010 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright 2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c448t-b00f8bbcadf17ee3a69bafa276e73a3cd03f1a45e2f81c2404a287cf3a66d04c3</citedby><cites>FETCH-LOGICAL-c448t-b00f8bbcadf17ee3a69bafa276e73a3cd03f1a45e2f81c2404a287cf3a66d04c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089609011602$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22830599$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20129791$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Asada, Masaki</creatorcontrib><creatorcontrib>Iwahashi, Maki</creatorcontrib><creatorcontrib>Obitsu, Tetsuo</creatorcontrib><creatorcontrib>Kinoshita, Atsushi</creatorcontrib><creatorcontrib>Nakai, Yoshihiko</creatorcontrib><creatorcontrib>Onoda, Takahiro</creatorcontrib><creatorcontrib>Nagase, Toshihiko</creatorcontrib><creatorcontrib>Tanaka, Motoyuki</creatorcontrib><creatorcontrib>Yamaura, Yoshiyuki</creatorcontrib><creatorcontrib>Takizawa, Hiroya</creatorcontrib><creatorcontrib>Yoshikawa, Ken</creatorcontrib><creatorcontrib>Sato, Kazutoyo</creatorcontrib><creatorcontrib>Narita, Masami</creatorcontrib><creatorcontrib>Ohuchida, Shuichi</creatorcontrib><creatorcontrib>Nakai, Hisao</creatorcontrib><creatorcontrib>Toda, Masaaki</creatorcontrib><title>3-(2-Aminocarbonylphenyl)propanoic acid analogs as potent and selective EP3 receptor antagonists. Part 2: Optimization of the side chains to improve in vitro and in vivo potencies</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>We identified a series of 3-[2-{[(3-methyl-1-phenylbutyl)amino]carbonyl}-4-(phenoxymethyl)phenyl]propanoic acid analogs as potent and selective EP3 receptor antagonists. Introduction of substituents into the two benzene nucleus resulted in the increased in vitro activities. Several compounds exhibited potent inhibitory effect against the PGE2-induced uterine contraction in pregnant rats.
A series of 3-[2-{[(3-methyl-1-phenylbutyl)amino]carbonyl}-4-(phenoxymethyl)phenyl]propanoic acid analogs were synthesized and evaluated for their in vitro potency. In most cases, introduction of one or two substituents into the two phenyl moieties resulted in the tendency of an increase or retention of in vitro activities. Several compounds, which showed excellent subtype selectivity, were evaluated for their inhibitory effect against PGE2-induced uterine contraction in pregnant rats, which is thought to be mediated by the EP3 receptor subtype. The structure–activity relationships (SARs) are also discussed.</description><subject>Animals</subject><subject>Antagonist</subject><subject>Biological and medical sciences</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>EP3 receptor</subject><subject>Female</subject><subject>Genital system. Reproduction</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Mass Spectrometry</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Pregnancy</subject><subject>Propionates - chemistry</subject><subject>Propionates - pharmacokinetics</subject><subject>Propionates - pharmacology</subject><subject>Rats</subject><subject>Receptors, Prostaglandin E - antagonists & inhibitors</subject><subject>Receptors, Prostaglandin E, EP3 Subtype</subject><subject>Uterine contraction</subject><subject>Uterine Contraction - drug effects</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAUhSMEokPhAdggbxB0keCfTGLDqqpaQKrULmBt3TjXHY8SO9iekcpr8YK4nQF2bGzZ_u451_dU1WtGG0ZZ92HbDLNpOKWqYbyhnXxSrVjbtbUQij2tVlR1sqZSdSfVi5S2lFLeKva8OuGUcdUrtqp-ifo9r89n54OBOAR_Py0bLOvZEsMCPjhDwLiRgIcp3CUCiSwho8_lZiQJJzTZ7ZFc3goS0eCSQyxPGe6CdymnhtxCzIR_JDdLdrP7CdkFT4IleYMkuRGJ2YDzieRA3Fxci5jzZO9yDI8ej4d9ONgah-ll9czClPDVcT-tvl9dfrv4Ul_ffP56cX5dm7aVuR4otXIYDIyW9YgCOjWABd532AsQZqTCMmjXyK1khre0BS57YwvYjbQ14rR6d9AtTf3YYcp6dsngNIHHsEu6F0KqtWKykOxAmhhSimj1Et0M8V4zqh-i0ltdotIPUWnGdYmq1Lw5qu-GGce_FX-yKcDbIwDJwGQjlN-nfxyXgq6VKtynA4dlFnuHUacyJW9wdCWQrMfg_tPGb16gtMI</recordid><startdate>20100215</startdate><enddate>20100215</enddate><creator>Asada, Masaki</creator><creator>Iwahashi, Maki</creator><creator>Obitsu, Tetsuo</creator><creator>Kinoshita, Atsushi</creator><creator>Nakai, Yoshihiko</creator><creator>Onoda, Takahiro</creator><creator>Nagase, Toshihiko</creator><creator>Tanaka, Motoyuki</creator><creator>Yamaura, Yoshiyuki</creator><creator>Takizawa, Hiroya</creator><creator>Yoshikawa, Ken</creator><creator>Sato, Kazutoyo</creator><creator>Narita, Masami</creator><creator>Ohuchida, Shuichi</creator><creator>Nakai, Hisao</creator><creator>Toda, Masaaki</creator><general>Elsevier Ltd</general><general>Elsevier</general><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><scope>7X8</scope></search><sort><creationdate>20100215</creationdate><title>3-(2-Aminocarbonylphenyl)propanoic acid analogs as potent and selective EP3 receptor antagonists. Part 2: Optimization of the side chains to improve in vitro and in vivo potencies</title><author>Asada, Masaki ; Iwahashi, Maki ; Obitsu, Tetsuo ; Kinoshita, Atsushi ; Nakai, Yoshihiko ; Onoda, Takahiro ; Nagase, Toshihiko ; Tanaka, Motoyuki ; Yamaura, Yoshiyuki ; Takizawa, Hiroya ; Yoshikawa, Ken ; Sato, Kazutoyo ; Narita, Masami ; Ohuchida, Shuichi ; Nakai, Hisao ; Toda, Masaaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c448t-b00f8bbcadf17ee3a69bafa276e73a3cd03f1a45e2f81c2404a287cf3a66d04c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Antagonist</topic><topic>Biological and medical sciences</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>EP3 receptor</topic><topic>Female</topic><topic>Genital system. Reproduction</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Mass Spectrometry</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Pregnancy</topic><topic>Propionates - chemistry</topic><topic>Propionates - pharmacokinetics</topic><topic>Propionates - pharmacology</topic><topic>Rats</topic><topic>Receptors, Prostaglandin E - antagonists & inhibitors</topic><topic>Receptors, Prostaglandin E, EP3 Subtype</topic><topic>Uterine contraction</topic><topic>Uterine Contraction - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Asada, Masaki</creatorcontrib><creatorcontrib>Iwahashi, Maki</creatorcontrib><creatorcontrib>Obitsu, Tetsuo</creatorcontrib><creatorcontrib>Kinoshita, Atsushi</creatorcontrib><creatorcontrib>Nakai, Yoshihiko</creatorcontrib><creatorcontrib>Onoda, Takahiro</creatorcontrib><creatorcontrib>Nagase, Toshihiko</creatorcontrib><creatorcontrib>Tanaka, Motoyuki</creatorcontrib><creatorcontrib>Yamaura, Yoshiyuki</creatorcontrib><creatorcontrib>Takizawa, Hiroya</creatorcontrib><creatorcontrib>Yoshikawa, Ken</creatorcontrib><creatorcontrib>Sato, Kazutoyo</creatorcontrib><creatorcontrib>Narita, Masami</creatorcontrib><creatorcontrib>Ohuchida, Shuichi</creatorcontrib><creatorcontrib>Nakai, Hisao</creatorcontrib><creatorcontrib>Toda, Masaaki</creatorcontrib><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><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Asada, Masaki</au><au>Iwahashi, Maki</au><au>Obitsu, Tetsuo</au><au>Kinoshita, Atsushi</au><au>Nakai, Yoshihiko</au><au>Onoda, Takahiro</au><au>Nagase, Toshihiko</au><au>Tanaka, Motoyuki</au><au>Yamaura, Yoshiyuki</au><au>Takizawa, Hiroya</au><au>Yoshikawa, Ken</au><au>Sato, Kazutoyo</au><au>Narita, Masami</au><au>Ohuchida, Shuichi</au><au>Nakai, Hisao</au><au>Toda, Masaaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>3-(2-Aminocarbonylphenyl)propanoic acid analogs as potent and selective EP3 receptor antagonists. 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A series of 3-[2-{[(3-methyl-1-phenylbutyl)amino]carbonyl}-4-(phenoxymethyl)phenyl]propanoic acid analogs were synthesized and evaluated for their in vitro potency. In most cases, introduction of one or two substituents into the two phenyl moieties resulted in the tendency of an increase or retention of in vitro activities. Several compounds, which showed excellent subtype selectivity, were evaluated for their inhibitory effect against PGE2-induced uterine contraction in pregnant rats, which is thought to be mediated by the EP3 receptor subtype. The structure–activity relationships (SARs) are also discussed.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>20129791</pmid><doi>10.1016/j.bmc.2009.12.068</doi><tpages>18</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry, 2010-02, Vol.18 (4), p.1641-1658 |
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| subjects | Animals Antagonist Biological and medical sciences CHO Cells Cricetinae Cricetulus EP3 receptor Female Genital system. Reproduction Magnetic Resonance Spectroscopy Mass Spectrometry Medical sciences Pharmacology. Drug treatments Pregnancy Propionates - chemistry Propionates - pharmacokinetics Propionates - pharmacology Rats Receptors, Prostaglandin E - antagonists & inhibitors Receptors, Prostaglandin E, EP3 Subtype Uterine contraction Uterine Contraction - drug effects |
| title | 3-(2-Aminocarbonylphenyl)propanoic acid analogs as potent and selective EP3 receptor antagonists. Part 2: Optimization of the side chains to improve in vitro and in vivo potencies |
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