Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human beta3-adrenergic receptor agonists with good oral bioavailability. Part I
A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investiga...
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| Veröffentlicht in: | Journal of medicinal chemistry 2008-03, Vol.51 (6), p.1925-1944 |
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| container_end_page | 1944 |
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| container_issue | 6 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 51 |
| creator | Imanishi, Masashi Tomishima, Yasuyo Itou, Shinji Hamashima, Hitoshi Nakajima, Yutaka Washizuka, Kenichi Sakurai, Minoru Matsui, Shigeo Imamura, Emiko Ueshima, Koji Yamamoto, Takao Yamamoto, Nobuhiro Ishikawa, Hirofumi Nakano, Keiko Unami, Naoko Hamada, Kaori Matsumura, Yasuhiro Takamura, Fujiko Hattori, Kouji |
| description | A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists. |
| doi_str_mv | 10.1021/jm701324c |
| format | Article |
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Part I</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Imanishi, Masashi ; Tomishima, Yasuyo ; Itou, Shinji ; Hamashima, Hitoshi ; Nakajima, Yutaka ; Washizuka, Kenichi ; Sakurai, Minoru ; Matsui, Shigeo ; Imamura, Emiko ; Ueshima, Koji ; Yamamoto, Takao ; Yamamoto, Nobuhiro ; Ishikawa, Hirofumi ; Nakano, Keiko ; Unami, Naoko ; Hamada, Kaori ; Matsumura, Yasuhiro ; Takamura, Fujiko ; Hattori, Kouji</creator><creatorcontrib>Imanishi, Masashi ; Tomishima, Yasuyo ; Itou, Shinji ; Hamashima, Hitoshi ; Nakajima, Yutaka ; Washizuka, Kenichi ; Sakurai, Minoru ; Matsui, Shigeo ; Imamura, Emiko ; Ueshima, Koji ; Yamamoto, Takao ; Yamamoto, Nobuhiro ; Ishikawa, Hirofumi ; Nakano, Keiko ; Unami, Naoko ; Hamada, Kaori ; Matsumura, Yasuhiro ; Takamura, Fujiko ; Hattori, Kouji</creatorcontrib><description>A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists.</description><identifier>ISSN: 0022-2623</identifier><identifier>DOI: 10.1021/jm701324c</identifier><identifier>PMID: 18307290</identifier><language>eng</language><publisher>United States</publisher><subject>Administration, Oral ; Adrenergic beta-3 Receptor Agonists ; Adrenergic beta-Agonists - chemical synthesis ; Adrenergic beta-Agonists - chemistry ; Adrenergic beta-Agonists - pharmacology ; Anesthesia ; Animals ; Benzoates - chemical synthesis ; Benzoates - chemistry ; Benzoates - pharmacology ; Biological Availability ; Biphenyl Compounds - chemistry ; Blood Pressure - drug effects ; Carbachol - antagonists & inhibitors ; Carbachol - pharmacology ; Dogs ; Drug Design ; Drug Evaluation, Preclinical ; Female ; Humans ; Injections, Intravenous ; Models, Animal ; Molecular Structure ; Stereoisomerism ; Structure-Activity Relationship ; Time Factors</subject><ispartof>Journal of medicinal chemistry, 2008-03, Vol.51 (6), p.1925-1944</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18307290$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Imanishi, Masashi</creatorcontrib><creatorcontrib>Tomishima, Yasuyo</creatorcontrib><creatorcontrib>Itou, Shinji</creatorcontrib><creatorcontrib>Hamashima, Hitoshi</creatorcontrib><creatorcontrib>Nakajima, Yutaka</creatorcontrib><creatorcontrib>Washizuka, Kenichi</creatorcontrib><creatorcontrib>Sakurai, Minoru</creatorcontrib><creatorcontrib>Matsui, Shigeo</creatorcontrib><creatorcontrib>Imamura, Emiko</creatorcontrib><creatorcontrib>Ueshima, Koji</creatorcontrib><creatorcontrib>Yamamoto, Takao</creatorcontrib><creatorcontrib>Yamamoto, Nobuhiro</creatorcontrib><creatorcontrib>Ishikawa, Hirofumi</creatorcontrib><creatorcontrib>Nakano, Keiko</creatorcontrib><creatorcontrib>Unami, Naoko</creatorcontrib><creatorcontrib>Hamada, Kaori</creatorcontrib><creatorcontrib>Matsumura, Yasuhiro</creatorcontrib><creatorcontrib>Takamura, Fujiko</creatorcontrib><creatorcontrib>Hattori, Kouji</creatorcontrib><title>Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human beta3-adrenergic receptor agonists with good oral bioavailability. Part I</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists.</description><subject>Administration, Oral</subject><subject>Adrenergic beta-3 Receptor Agonists</subject><subject>Adrenergic beta-Agonists - chemical synthesis</subject><subject>Adrenergic beta-Agonists - chemistry</subject><subject>Adrenergic beta-Agonists - pharmacology</subject><subject>Anesthesia</subject><subject>Animals</subject><subject>Benzoates - chemical synthesis</subject><subject>Benzoates - chemistry</subject><subject>Benzoates - pharmacology</subject><subject>Biological Availability</subject><subject>Biphenyl Compounds - chemistry</subject><subject>Blood Pressure - drug effects</subject><subject>Carbachol - antagonists & inhibitors</subject><subject>Carbachol - pharmacology</subject><subject>Dogs</subject><subject>Drug Design</subject><subject>Drug Evaluation, Preclinical</subject><subject>Female</subject><subject>Humans</subject><subject>Injections, Intravenous</subject><subject>Models, Animal</subject><subject>Molecular Structure</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Time Factors</subject><issn>0022-2623</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kM1OAjEUhbvQCKILX8B05W6wPwNTlgb_SEh0wZ7c6dxCyUw7tgWDT-RjWiOu7s0937knOYTccDbmTPD7XVcxLkWpz8iQMSEKMRVyQC5j3DHGJBfyggy4kqwSMzYk3482an_AcKTeUKAu7y2NGCzG30tt-y26Y0trdF_eagraNrTJ-gGSPWQIIu19QpcouCY7W9S_At3uO3DZlkAW0AR0GDbZH1Bjn3ygsPHOxhTpp01buvG-oT5ADrIeDmBbqG1r03FM3yEkurgi5wbaiNenOSKr56fV_LVYvr0s5g_Lop-UrKgQKyWkMmAmmktWT7gs65obUFrxpirlVILQZsoVCDkTTCnDRVUaw0qpdC1H5O7vbR_8xx5jWne5IGxbcOj3cT1VbDaZCZXB2xO4rzts1n2wHYTj-r9a-QNvD3tw</recordid><startdate>20080327</startdate><enddate>20080327</enddate><creator>Imanishi, Masashi</creator><creator>Tomishima, Yasuyo</creator><creator>Itou, Shinji</creator><creator>Hamashima, Hitoshi</creator><creator>Nakajima, Yutaka</creator><creator>Washizuka, Kenichi</creator><creator>Sakurai, Minoru</creator><creator>Matsui, Shigeo</creator><creator>Imamura, Emiko</creator><creator>Ueshima, Koji</creator><creator>Yamamoto, Takao</creator><creator>Yamamoto, Nobuhiro</creator><creator>Ishikawa, Hirofumi</creator><creator>Nakano, Keiko</creator><creator>Unami, Naoko</creator><creator>Hamada, Kaori</creator><creator>Matsumura, Yasuhiro</creator><creator>Takamura, Fujiko</creator><creator>Hattori, Kouji</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>20080327</creationdate><title>Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human beta3-adrenergic receptor agonists with good oral bioavailability. Part I</title><author>Imanishi, Masashi ; Tomishima, Yasuyo ; Itou, Shinji ; Hamashima, Hitoshi ; Nakajima, Yutaka ; Washizuka, Kenichi ; Sakurai, Minoru ; Matsui, Shigeo ; Imamura, Emiko ; Ueshima, Koji ; Yamamoto, Takao ; Yamamoto, Nobuhiro ; Ishikawa, Hirofumi ; Nakano, Keiko ; Unami, Naoko ; Hamada, Kaori ; Matsumura, Yasuhiro ; Takamura, Fujiko ; Hattori, Kouji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p540-7ee78238faf5c130b5134bb1fa8c81d74363a2cf618a2392088f1274ff0438cb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Administration, Oral</topic><topic>Adrenergic beta-3 Receptor Agonists</topic><topic>Adrenergic beta-Agonists - chemical synthesis</topic><topic>Adrenergic beta-Agonists - chemistry</topic><topic>Adrenergic beta-Agonists - pharmacology</topic><topic>Anesthesia</topic><topic>Animals</topic><topic>Benzoates - chemical synthesis</topic><topic>Benzoates - chemistry</topic><topic>Benzoates - pharmacology</topic><topic>Biological Availability</topic><topic>Biphenyl Compounds - chemistry</topic><topic>Blood Pressure - drug effects</topic><topic>Carbachol - antagonists & inhibitors</topic><topic>Carbachol - pharmacology</topic><topic>Dogs</topic><topic>Drug Design</topic><topic>Drug Evaluation, Preclinical</topic><topic>Female</topic><topic>Humans</topic><topic>Injections, Intravenous</topic><topic>Models, Animal</topic><topic>Molecular Structure</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Imanishi, Masashi</creatorcontrib><creatorcontrib>Tomishima, Yasuyo</creatorcontrib><creatorcontrib>Itou, Shinji</creatorcontrib><creatorcontrib>Hamashima, Hitoshi</creatorcontrib><creatorcontrib>Nakajima, Yutaka</creatorcontrib><creatorcontrib>Washizuka, Kenichi</creatorcontrib><creatorcontrib>Sakurai, Minoru</creatorcontrib><creatorcontrib>Matsui, Shigeo</creatorcontrib><creatorcontrib>Imamura, Emiko</creatorcontrib><creatorcontrib>Ueshima, Koji</creatorcontrib><creatorcontrib>Yamamoto, Takao</creatorcontrib><creatorcontrib>Yamamoto, Nobuhiro</creatorcontrib><creatorcontrib>Ishikawa, Hirofumi</creatorcontrib><creatorcontrib>Nakano, Keiko</creatorcontrib><creatorcontrib>Unami, Naoko</creatorcontrib><creatorcontrib>Hamada, Kaori</creatorcontrib><creatorcontrib>Matsumura, Yasuhiro</creatorcontrib><creatorcontrib>Takamura, Fujiko</creatorcontrib><creatorcontrib>Hattori, Kouji</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Imanishi, Masashi</au><au>Tomishima, Yasuyo</au><au>Itou, Shinji</au><au>Hamashima, Hitoshi</au><au>Nakajima, Yutaka</au><au>Washizuka, Kenichi</au><au>Sakurai, Minoru</au><au>Matsui, Shigeo</au><au>Imamura, Emiko</au><au>Ueshima, Koji</au><au>Yamamoto, Takao</au><au>Yamamoto, Nobuhiro</au><au>Ishikawa, Hirofumi</au><au>Nakano, Keiko</au><au>Unami, Naoko</au><au>Hamada, Kaori</au><au>Matsumura, Yasuhiro</au><au>Takamura, Fujiko</au><au>Hattori, Kouji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human beta3-adrenergic receptor agonists with good oral bioavailability. Part I</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>2008-03-27</date><risdate>2008</risdate><volume>51</volume><issue>6</issue><spage>1925</spage><epage>1944</epage><pages>1925-1944</pages><issn>0022-2623</issn><abstract>A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists.</abstract><cop>United States</cop><pmid>18307290</pmid><doi>10.1021/jm701324c</doi><tpages>20</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2008-03, Vol.51 (6), p.1925-1944 |
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| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Administration, Oral Adrenergic beta-3 Receptor Agonists Adrenergic beta-Agonists - chemical synthesis Adrenergic beta-Agonists - chemistry Adrenergic beta-Agonists - pharmacology Anesthesia Animals Benzoates - chemical synthesis Benzoates - chemistry Benzoates - pharmacology Biological Availability Biphenyl Compounds - chemistry Blood Pressure - drug effects Carbachol - antagonists & inhibitors Carbachol - pharmacology Dogs Drug Design Drug Evaluation, Preclinical Female Humans Injections, Intravenous Models, Animal Molecular Structure Stereoisomerism Structure-Activity Relationship Time Factors |
| title | Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human beta3-adrenergic receptor agonists with good oral bioavailability. Part I |
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