Dual CCK-A and CCK-B Receptor Antagonists (II). Preparation and Structure Activity Relationships of 5-Alkyl-9-methyl-1, 4-benzodiazepines and Discovery of FR208419
In our continuing research for dual CCK-A and -B antagonists, according to our hypothesis that dual CCK-A and -B antagonists should be more efficacious than selective CCK-A antagonists for the treatment of panreatitis, we have prepared various 5-alkyl-9-methyl-1, 4-benzodiazepines. From the compound...
Gespeichert in:
| Veröffentlicht in: | Chemical & pharmaceutical bulletin 2000/01/01, Vol.48(1), pp.1-15 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 15 |
|---|---|
| container_issue | 1 |
| container_start_page | 1 |
| container_title | Chemical & pharmaceutical bulletin |
| container_volume | 48 |
| creator | TABUCHI, Seiichiro ITO, Harunobu SOGABE, Hajime KUNO, Masako KINOSHITA, Takayoshi TATUMI, Ikuyo YAMAMOTO, Naoko MITSUI, Hitoshi SATOH, Yoshinari |
| description | In our continuing research for dual CCK-A and -B antagonists, according to our hypothesis that dual CCK-A and -B antagonists should be more efficacious than selective CCK-A antagonists for the treatment of panreatitis, we have prepared various 5-alkyl-9-methyl-1, 4-benzodiazepines. From the compounds prepared, 1-cyclo-hexyl-carbonylmethyl-5-ethyl-9-methyl-3-(m-tolylureido)-2-oxo--1, 4-benzodiazepine, (40) was selected as a candidate for development due to its well-balanced high affinity for both receptors. The R-enantiomer of 40, (R)-40 (FR 208419), had 27-fold higher affinity for the CCK-A receprot and 8-fold more potent CCK-B receptor binding activity than (S)-40.The biological activity after p.o.administration of (R)-40, estimated from the ID50 value (0.23 mg/kg p.o.) obtained by preliminary evaluation by gastric emptying effects, is considered to be high enough for further development. This compound is now undergoing further biological evaluations with a view to clinical development. |
| doi_str_mv | 10.1248/cpb.48.1 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_70952531</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3133382651</sourcerecordid><originalsourceid>FETCH-LOGICAL-c620t-c0276a0acf6d332e4d5cdcd360c956dc214a2d40e76149a51c6316d201d1e8ad3</originalsourceid><addsrcrecordid>eNpdkW9r1EAQxhex2LMKfgJZsEgL5tx_2SQv49XqYUGp-jrs7U68PXNJ3N0Url_HL-omOaz4Zmbg-c0zAw9CLyhZUibyt7rfLEW-pI_QgnKRJSlj_DFaEEKKhHHJT9FT73eEsJRk_Ak6pSQjqZD5Av2-GlSDV6tPSYlVa6bpHb4FDX3oHC7boH50rfXB44v1-nKJvzjolVPBdu208DW4QYfBAS51sHc2HOJ2M-l-a3uPuxqnSdn8PDRJkewhbONA32CRbKC974xV99DbFvzkdmW97u7AHca161tGckGLZ-ikVo2H58d-hr5fv_-2-pjcfP6wXpU3iZaMhEQTlklFlK6l4ZyBMKk22nBJdJFKoxkVihlBIJNUFCqlWnIqDSPUUMiV4Wfo9ezbu-7XAD5U-_gONI1qoRt8lZEiZSmnEXz1H7jrBtfG3yoqJOGMFVxE6mKmtOu8d1BXvbN75Q4VJdUYWxVjq2IbDV8eDYfNHsw_4JxTBM6PgPJaNbVTrbb-gWN5TvLRp5yxnY-5wV9duWB1A-NBWqT5dHQu9EHbKldBy_8AiS20Qg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1460322934</pqid></control><display><type>article</type><title>Dual CCK-A and CCK-B Receptor Antagonists (II). Preparation and Structure Activity Relationships of 5-Alkyl-9-methyl-1, 4-benzodiazepines and Discovery of FR208419</title><source>J-STAGE Free</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Free Full-Text Journals in Chemistry</source><creator>TABUCHI, Seiichiro ; ITO, Harunobu ; SOGABE, Hajime ; KUNO, Masako ; KINOSHITA, Takayoshi ; TATUMI, Ikuyo ; YAMAMOTO, Naoko ; MITSUI, Hitoshi ; SATOH, Yoshinari</creator><creatorcontrib>TABUCHI, Seiichiro ; ITO, Harunobu ; SOGABE, Hajime ; KUNO, Masako ; KINOSHITA, Takayoshi ; TATUMI, Ikuyo ; YAMAMOTO, Naoko ; MITSUI, Hitoshi ; SATOH, Yoshinari</creatorcontrib><description>In our continuing research for dual CCK-A and -B antagonists, according to our hypothesis that dual CCK-A and -B antagonists should be more efficacious than selective CCK-A antagonists for the treatment of panreatitis, we have prepared various 5-alkyl-9-methyl-1, 4-benzodiazepines. From the compounds prepared, 1-cyclo-hexyl-carbonylmethyl-5-ethyl-9-methyl-3-(m-tolylureido)-2-oxo--1, 4-benzodiazepine, (40) was selected as a candidate for development due to its well-balanced high affinity for both receptors. The R-enantiomer of 40, (R)-40 (FR 208419), had 27-fold higher affinity for the CCK-A receprot and 8-fold more potent CCK-B receptor binding activity than (S)-40.The biological activity after p.o.administration of (R)-40, estimated from the ID50 value (0.23 mg/kg p.o.) obtained by preliminary evaluation by gastric emptying effects, is considered to be high enough for further development. This compound is now undergoing further biological evaluations with a view to clinical development.</description><identifier>ISSN: 0009-2363</identifier><identifier>EISSN: 1347-5223</identifier><identifier>DOI: 10.1248/cpb.48.1</identifier><identifier>PMID: 10705468</identifier><identifier>CODEN: CPBTAL</identifier><language>eng</language><publisher>Tokyo: The Pharmaceutical Society of Japan</publisher><subject>(3R)-1-cyclohexylcarbonyl-methyl-5-ethyl-9-methyl-2-oxo-[3-(m-tolyl)ureido]-1, 4-benzodiazepine ; 5-alkyl-9-methyl-1, 4-benzodiazepine ; Animals ; Benzodiazepinones - chemical synthesis ; Benzodiazepinones - pharmacology ; Biological and medical sciences ; Cerebral Cortex - drug effects ; Cerebral Cortex - metabolism ; Digestive system ; dual CCK-A and -B antagonist ; Gastric Emptying - drug effects ; Guinea Pigs ; In Vitro Techniques ; Indicators and Reagents ; Magnetic Resonance Spectroscopy ; Medical sciences ; Mice ; Models, Molecular ; Pancreas - drug effects ; Pancreas - metabolism ; pancreatitis ; Pharmacology. Drug treatments ; Phenylurea Compounds - chemical synthesis ; Phenylurea Compounds - pharmacology ; Rats ; Receptor, Cholecystokinin A ; Receptor, Cholecystokinin B ; Receptors, Cholecystokinin - antagonists & inhibitors ; Sincalide - metabolism ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Chemical and Pharmaceutical Bulletin, 2000/01/01, Vol.48(1), pp.1-15</ispartof><rights>The Pharmaceutical Society of Japan</rights><rights>2000 INIST-CNRS</rights><rights>Copyright Japan Science and Technology Agency 2000</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c620t-c0276a0acf6d332e4d5cdcd360c956dc214a2d40e76149a51c6316d201d1e8ad3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1881,4022,27922,27923,27924</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1288081$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10705468$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>TABUCHI, Seiichiro</creatorcontrib><creatorcontrib>ITO, Harunobu</creatorcontrib><creatorcontrib>SOGABE, Hajime</creatorcontrib><creatorcontrib>KUNO, Masako</creatorcontrib><creatorcontrib>KINOSHITA, Takayoshi</creatorcontrib><creatorcontrib>TATUMI, Ikuyo</creatorcontrib><creatorcontrib>YAMAMOTO, Naoko</creatorcontrib><creatorcontrib>MITSUI, Hitoshi</creatorcontrib><creatorcontrib>SATOH, Yoshinari</creatorcontrib><title>Dual CCK-A and CCK-B Receptor Antagonists (II). Preparation and Structure Activity Relationships of 5-Alkyl-9-methyl-1, 4-benzodiazepines and Discovery of FR208419</title><title>Chemical & pharmaceutical bulletin</title><addtitle>Chem. Pharm. Bull.</addtitle><description>In our continuing research for dual CCK-A and -B antagonists, according to our hypothesis that dual CCK-A and -B antagonists should be more efficacious than selective CCK-A antagonists for the treatment of panreatitis, we have prepared various 5-alkyl-9-methyl-1, 4-benzodiazepines. From the compounds prepared, 1-cyclo-hexyl-carbonylmethyl-5-ethyl-9-methyl-3-(m-tolylureido)-2-oxo--1, 4-benzodiazepine, (40) was selected as a candidate for development due to its well-balanced high affinity for both receptors. The R-enantiomer of 40, (R)-40 (FR 208419), had 27-fold higher affinity for the CCK-A receprot and 8-fold more potent CCK-B receptor binding activity than (S)-40.The biological activity after p.o.administration of (R)-40, estimated from the ID50 value (0.23 mg/kg p.o.) obtained by preliminary evaluation by gastric emptying effects, is considered to be high enough for further development. This compound is now undergoing further biological evaluations with a view to clinical development.</description><subject>(3R)-1-cyclohexylcarbonyl-methyl-5-ethyl-9-methyl-2-oxo-[3-(m-tolyl)ureido]-1, 4-benzodiazepine</subject><subject>5-alkyl-9-methyl-1, 4-benzodiazepine</subject><subject>Animals</subject><subject>Benzodiazepinones - chemical synthesis</subject><subject>Benzodiazepinones - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cerebral Cortex - drug effects</subject><subject>Cerebral Cortex - metabolism</subject><subject>Digestive system</subject><subject>dual CCK-A and -B antagonist</subject><subject>Gastric Emptying - drug effects</subject><subject>Guinea Pigs</subject><subject>In Vitro Techniques</subject><subject>Indicators and Reagents</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Pancreas - drug effects</subject><subject>Pancreas - metabolism</subject><subject>pancreatitis</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenylurea Compounds - chemical synthesis</subject><subject>Phenylurea Compounds - pharmacology</subject><subject>Rats</subject><subject>Receptor, Cholecystokinin A</subject><subject>Receptor, Cholecystokinin B</subject><subject>Receptors, Cholecystokinin - antagonists & inhibitors</subject><subject>Sincalide - metabolism</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkW9r1EAQxhex2LMKfgJZsEgL5tx_2SQv49XqYUGp-jrs7U68PXNJ3N0Url_HL-omOaz4Zmbg-c0zAw9CLyhZUibyt7rfLEW-pI_QgnKRJSlj_DFaEEKKhHHJT9FT73eEsJRk_Ak6pSQjqZD5Av2-GlSDV6tPSYlVa6bpHb4FDX3oHC7boH50rfXB44v1-nKJvzjolVPBdu208DW4QYfBAS51sHc2HOJ2M-l-a3uPuxqnSdn8PDRJkewhbONA32CRbKC974xV99DbFvzkdmW97u7AHca161tGckGLZ-ikVo2H58d-hr5fv_-2-pjcfP6wXpU3iZaMhEQTlklFlK6l4ZyBMKk22nBJdJFKoxkVihlBIJNUFCqlWnIqDSPUUMiV4Wfo9ezbu-7XAD5U-_gONI1qoRt8lZEiZSmnEXz1H7jrBtfG3yoqJOGMFVxE6mKmtOu8d1BXvbN75Q4VJdUYWxVjq2IbDV8eDYfNHsw_4JxTBM6PgPJaNbVTrbb-gWN5TvLRp5yxnY-5wV9duWB1A-NBWqT5dHQu9EHbKldBy_8AiS20Qg</recordid><startdate>20000101</startdate><enddate>20000101</enddate><creator>TABUCHI, Seiichiro</creator><creator>ITO, Harunobu</creator><creator>SOGABE, Hajime</creator><creator>KUNO, Masako</creator><creator>KINOSHITA, Takayoshi</creator><creator>TATUMI, Ikuyo</creator><creator>YAMAMOTO, Naoko</creator><creator>MITSUI, Hitoshi</creator><creator>SATOH, Yoshinari</creator><general>The Pharmaceutical Society of Japan</general><general>Maruzen</general><general>Japan Science and Technology Agency</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>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20000101</creationdate><title>Dual CCK-A and CCK-B Receptor Antagonists (II). Preparation and Structure Activity Relationships of 5-Alkyl-9-methyl-1, 4-benzodiazepines and Discovery of FR208419</title><author>TABUCHI, Seiichiro ; ITO, Harunobu ; SOGABE, Hajime ; KUNO, Masako ; KINOSHITA, Takayoshi ; TATUMI, Ikuyo ; YAMAMOTO, Naoko ; MITSUI, Hitoshi ; SATOH, Yoshinari</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c620t-c0276a0acf6d332e4d5cdcd360c956dc214a2d40e76149a51c6316d201d1e8ad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>(3R)-1-cyclohexylcarbonyl-methyl-5-ethyl-9-methyl-2-oxo-[3-(m-tolyl)ureido]-1, 4-benzodiazepine</topic><topic>5-alkyl-9-methyl-1, 4-benzodiazepine</topic><topic>Animals</topic><topic>Benzodiazepinones - chemical synthesis</topic><topic>Benzodiazepinones - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cerebral Cortex - drug effects</topic><topic>Cerebral Cortex - metabolism</topic><topic>Digestive system</topic><topic>dual CCK-A and -B antagonist</topic><topic>Gastric Emptying - drug effects</topic><topic>Guinea Pigs</topic><topic>In Vitro Techniques</topic><topic>Indicators and Reagents</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>Pancreas - drug effects</topic><topic>Pancreas - metabolism</topic><topic>pancreatitis</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenylurea Compounds - chemical synthesis</topic><topic>Phenylurea Compounds - pharmacology</topic><topic>Rats</topic><topic>Receptor, Cholecystokinin A</topic><topic>Receptor, Cholecystokinin B</topic><topic>Receptors, Cholecystokinin - antagonists & inhibitors</topic><topic>Sincalide - metabolism</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>TABUCHI, Seiichiro</creatorcontrib><creatorcontrib>ITO, Harunobu</creatorcontrib><creatorcontrib>SOGABE, Hajime</creatorcontrib><creatorcontrib>KUNO, Masako</creatorcontrib><creatorcontrib>KINOSHITA, Takayoshi</creatorcontrib><creatorcontrib>TATUMI, Ikuyo</creatorcontrib><creatorcontrib>YAMAMOTO, Naoko</creatorcontrib><creatorcontrib>MITSUI, Hitoshi</creatorcontrib><creatorcontrib>SATOH, Yoshinari</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>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chemical & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>TABUCHI, Seiichiro</au><au>ITO, Harunobu</au><au>SOGABE, Hajime</au><au>KUNO, Masako</au><au>KINOSHITA, Takayoshi</au><au>TATUMI, Ikuyo</au><au>YAMAMOTO, Naoko</au><au>MITSUI, Hitoshi</au><au>SATOH, Yoshinari</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dual CCK-A and CCK-B Receptor Antagonists (II). Preparation and Structure Activity Relationships of 5-Alkyl-9-methyl-1, 4-benzodiazepines and Discovery of FR208419</atitle><jtitle>Chemical & pharmaceutical bulletin</jtitle><addtitle>Chem. Pharm. Bull.</addtitle><date>2000-01-01</date><risdate>2000</risdate><volume>48</volume><issue>1</issue><spage>1</spage><epage>15</epage><pages>1-15</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><coden>CPBTAL</coden><abstract>In our continuing research for dual CCK-A and -B antagonists, according to our hypothesis that dual CCK-A and -B antagonists should be more efficacious than selective CCK-A antagonists for the treatment of panreatitis, we have prepared various 5-alkyl-9-methyl-1, 4-benzodiazepines. From the compounds prepared, 1-cyclo-hexyl-carbonylmethyl-5-ethyl-9-methyl-3-(m-tolylureido)-2-oxo--1, 4-benzodiazepine, (40) was selected as a candidate for development due to its well-balanced high affinity for both receptors. The R-enantiomer of 40, (R)-40 (FR 208419), had 27-fold higher affinity for the CCK-A receprot and 8-fold more potent CCK-B receptor binding activity than (S)-40.The biological activity after p.o.administration of (R)-40, estimated from the ID50 value (0.23 mg/kg p.o.) obtained by preliminary evaluation by gastric emptying effects, is considered to be high enough for further development. This compound is now undergoing further biological evaluations with a view to clinical development.</abstract><cop>Tokyo</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>10705468</pmid><doi>10.1248/cpb.48.1</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0009-2363 |
| ispartof | Chemical and Pharmaceutical Bulletin, 2000/01/01, Vol.48(1), pp.1-15 |
| issn | 0009-2363 1347-5223 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_70952531 |
| source | J-STAGE Free; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Free Full-Text Journals in Chemistry |
| subjects | (3R)-1-cyclohexylcarbonyl-methyl-5-ethyl-9-methyl-2-oxo-[3-(m-tolyl)ureido]-1, 4-benzodiazepine 5-alkyl-9-methyl-1, 4-benzodiazepine Animals Benzodiazepinones - chemical synthesis Benzodiazepinones - pharmacology Biological and medical sciences Cerebral Cortex - drug effects Cerebral Cortex - metabolism Digestive system dual CCK-A and -B antagonist Gastric Emptying - drug effects Guinea Pigs In Vitro Techniques Indicators and Reagents Magnetic Resonance Spectroscopy Medical sciences Mice Models, Molecular Pancreas - drug effects Pancreas - metabolism pancreatitis Pharmacology. Drug treatments Phenylurea Compounds - chemical synthesis Phenylurea Compounds - pharmacology Rats Receptor, Cholecystokinin A Receptor, Cholecystokinin B Receptors, Cholecystokinin - antagonists & inhibitors Sincalide - metabolism Stereoisomerism Structure-Activity Relationship |
| title | Dual CCK-A and CCK-B Receptor Antagonists (II). Preparation and Structure Activity Relationships of 5-Alkyl-9-methyl-1, 4-benzodiazepines and Discovery of FR208419 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-12T04%3A20%3A59IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Dual%20CCK-A%20and%20CCK-B%20Receptor%20Antagonists%20(II).%20Preparation%20and%20Structure%20Activity%20Relationships%20of%205-Alkyl-9-methyl-1,%204-benzodiazepines%20and%20Discovery%20of%20FR208419&rft.jtitle=Chemical%20&%20pharmaceutical%20bulletin&rft.au=TABUCHI,%20Seiichiro&rft.date=2000-01-01&rft.volume=48&rft.issue=1&rft.spage=1&rft.epage=15&rft.pages=1-15&rft.issn=0009-2363&rft.eissn=1347-5223&rft.coden=CPBTAL&rft_id=info:doi/10.1248/cpb.48.1&rft_dat=%3Cproquest_cross%3E3133382651%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1460322934&rft_id=info:pmid/10705468&rfr_iscdi=true |