Identification of 4-amino-2-cyclohexylaminoquinazolines as metabolically stable melanin-concentrating hormone receptor 1 antagonists
Through an optimization of the distance between two key pharmacophore features, 4-amino-2-cyclohexylaminoquinazolines were identified as potent melanin-concentrating hormone receptor 1 (MCH-R1) antagonists, leading to the discovery of ATC0065. The optimization of the distance between two key pharmac...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2006-05, Vol.14 (10), p.3307-3319 |
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| creator | Kanuma, Kosuke Omodera, Katsunori Nishiguchi, Mariko Funakoshi, Takeo Chaki, Shigeyuki Nagase, Yasuko Iida, Izumi Yamaguchi, Jun-ichi Semple, Graeme Tran, Thuy-Anh Sekiguchi, Yoshinori |
| description | Through an optimization of the distance between two key pharmacophore features, 4-amino-2-cyclohexylaminoquinazolines were identified as potent melanin-concentrating hormone receptor 1 (MCH-R1) antagonists, leading to the discovery of ATC0065.
The optimization of the distance between two key pharmacophore features within our first hit compounds
1a and
2a led to the identification of a new class of potent non-peptidic antagonists for the MCH-R1, based around 4-amino-2-cyclohexylaminoquinazolines. In particular, ATC0065 (
2c),
N
2-[
cis-4-({2-[4-Bromo-2-(trifluoromethoxy)phenyl]ethyl}amino)cyclohexyl]-
N
4,
N
4-dimethylquinazoline-2,4-diamine dihydrochloride, bound with high affinity to the MCH-R1 (IC
50 value of 16 nM) and showed good metabolic stability in liver microsomes from human and rat. |
| doi_str_mv | 10.1016/j.bmc.2005.12.052 |
| format | Article |
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The optimization of the distance between two key pharmacophore features within our first hit compounds
1a and
2a led to the identification of a new class of potent non-peptidic antagonists for the MCH-R1, based around 4-amino-2-cyclohexylaminoquinazolines. In particular, ATC0065 (
2c),
N
2-[
cis-4-({2-[4-Bromo-2-(trifluoromethoxy)phenyl]ethyl}amino)cyclohexyl]-
N
4,
N
4-dimethylquinazoline-2,4-diamine dihydrochloride, bound with high affinity to the MCH-R1 (IC
50 value of 16 nM) and showed good metabolic stability in liver microsomes from human and rat.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2005.12.052</identifier><identifier>PMID: 16434202</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Animals ; ATC0065 ; Biological and medical sciences ; Hormones. Endocrine system ; Humans ; Lethal Dose 50 ; MCH-R1 antagonists ; Medical sciences ; Melanin-concentrating hormone receptor 1 antagonists ; Microsomes - metabolism ; Molecular Structure ; Pharmacology. Drug treatments ; Quinazolines - chemistry ; Quinazolines - pharmacology ; Rats ; Receptors, Somatostatin - antagonists & inhibitors ; Receptors, Somatostatin - chemistry</subject><ispartof>Bioorganic & medicinal chemistry, 2006-05, Vol.14 (10), p.3307-3319</ispartof><rights>2006 Elsevier Ltd</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-5af3279308102b530f9113000572cff7031796aef0b9b9368f2d58b2e5d760783</citedby><cites>FETCH-LOGICAL-c412t-5af3279308102b530f9113000572cff7031796aef0b9b9368f2d58b2e5d760783</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S096808960600006X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17667855$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16434202$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kanuma, Kosuke</creatorcontrib><creatorcontrib>Omodera, Katsunori</creatorcontrib><creatorcontrib>Nishiguchi, Mariko</creatorcontrib><creatorcontrib>Funakoshi, Takeo</creatorcontrib><creatorcontrib>Chaki, Shigeyuki</creatorcontrib><creatorcontrib>Nagase, Yasuko</creatorcontrib><creatorcontrib>Iida, Izumi</creatorcontrib><creatorcontrib>Yamaguchi, Jun-ichi</creatorcontrib><creatorcontrib>Semple, Graeme</creatorcontrib><creatorcontrib>Tran, Thuy-Anh</creatorcontrib><creatorcontrib>Sekiguchi, Yoshinori</creatorcontrib><title>Identification of 4-amino-2-cyclohexylaminoquinazolines as metabolically stable melanin-concentrating hormone receptor 1 antagonists</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>Through an optimization of the distance between two key pharmacophore features, 4-amino-2-cyclohexylaminoquinazolines were identified as potent melanin-concentrating hormone receptor 1 (MCH-R1) antagonists, leading to the discovery of ATC0065.
The optimization of the distance between two key pharmacophore features within our first hit compounds
1a and
2a led to the identification of a new class of potent non-peptidic antagonists for the MCH-R1, based around 4-amino-2-cyclohexylaminoquinazolines. In particular, ATC0065 (
2c),
N
2-[
cis-4-({2-[4-Bromo-2-(trifluoromethoxy)phenyl]ethyl}amino)cyclohexyl]-
N
4,
N
4-dimethylquinazoline-2,4-diamine dihydrochloride, bound with high affinity to the MCH-R1 (IC
50 value of 16 nM) and showed good metabolic stability in liver microsomes from human and rat.</description><subject>Animals</subject><subject>ATC0065</subject><subject>Biological and medical sciences</subject><subject>Hormones. Endocrine system</subject><subject>Humans</subject><subject>Lethal Dose 50</subject><subject>MCH-R1 antagonists</subject><subject>Medical sciences</subject><subject>Melanin-concentrating hormone receptor 1 antagonists</subject><subject>Microsomes - metabolism</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Quinazolines - chemistry</subject><subject>Quinazolines - pharmacology</subject><subject>Rats</subject><subject>Receptors, Somatostatin - antagonists & inhibitors</subject><subject>Receptors, Somatostatin - chemistry</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1v1DAQhi1ERZfCD-CCcoFbwoyd2Ik4oYqPSpW4tGfLcezWq8Re7CzqcuaHd8qu1Bun0YyeeTXzMPYOoUFA-WnbjIttOEDXIG-g4y_YBlvZ1kIM-JJtYJB9Df0gz9nrUrYAwNsBX7FzlK1oOfAN-3s1ubgGH6xZQ4pV8lVbmyXEVPPaHuyc7t3DYf43-bUP0fxJc4iuVKZUi1vNSK0183yoCjWzo-FsYoi1TdFScqbYeFfdp7yk6KrsrNutKVdYmbiauxRDWcsbdubNXNzbU71gt9--3lz-qK9_fr-6_HJd2xb5WnfGC64GAT0CHzsBfkAU9FWnuPVegUA1SOM8jMM4CNl7PnX9yF03KQmqFxfs4zF3l-kZV1a9hGLdTBe7tC8aFSrSAgTiEbQ5lZKd17scFpMPGkE_qddbTer1k3qNXJN62nl_Ct-Pi5ueN06uCfhwAkwhZT6baEN55pSUqu864j4fOUcqfgeXdbHBkc0pkL5VTyn854xHAZGjAw</recordid><startdate>20060515</startdate><enddate>20060515</enddate><creator>Kanuma, Kosuke</creator><creator>Omodera, Katsunori</creator><creator>Nishiguchi, Mariko</creator><creator>Funakoshi, Takeo</creator><creator>Chaki, Shigeyuki</creator><creator>Nagase, Yasuko</creator><creator>Iida, Izumi</creator><creator>Yamaguchi, Jun-ichi</creator><creator>Semple, Graeme</creator><creator>Tran, Thuy-Anh</creator><creator>Sekiguchi, Yoshinori</creator><general>Elsevier Ltd</general><general>Elsevier Science</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20060515</creationdate><title>Identification of 4-amino-2-cyclohexylaminoquinazolines as metabolically stable melanin-concentrating hormone receptor 1 antagonists</title><author>Kanuma, Kosuke ; Omodera, Katsunori ; Nishiguchi, Mariko ; Funakoshi, Takeo ; Chaki, Shigeyuki ; Nagase, Yasuko ; Iida, Izumi ; Yamaguchi, Jun-ichi ; Semple, Graeme ; Tran, Thuy-Anh ; Sekiguchi, Yoshinori</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-5af3279308102b530f9113000572cff7031796aef0b9b9368f2d58b2e5d760783</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>ATC0065</topic><topic>Biological and medical sciences</topic><topic>Hormones. Endocrine system</topic><topic>Humans</topic><topic>Lethal Dose 50</topic><topic>MCH-R1 antagonists</topic><topic>Medical sciences</topic><topic>Melanin-concentrating hormone receptor 1 antagonists</topic><topic>Microsomes - metabolism</topic><topic>Molecular Structure</topic><topic>Pharmacology. Drug treatments</topic><topic>Quinazolines - chemistry</topic><topic>Quinazolines - pharmacology</topic><topic>Rats</topic><topic>Receptors, Somatostatin - antagonists & inhibitors</topic><topic>Receptors, Somatostatin - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kanuma, Kosuke</creatorcontrib><creatorcontrib>Omodera, Katsunori</creatorcontrib><creatorcontrib>Nishiguchi, Mariko</creatorcontrib><creatorcontrib>Funakoshi, Takeo</creatorcontrib><creatorcontrib>Chaki, Shigeyuki</creatorcontrib><creatorcontrib>Nagase, Yasuko</creatorcontrib><creatorcontrib>Iida, Izumi</creatorcontrib><creatorcontrib>Yamaguchi, Jun-ichi</creatorcontrib><creatorcontrib>Semple, Graeme</creatorcontrib><creatorcontrib>Tran, Thuy-Anh</creatorcontrib><creatorcontrib>Sekiguchi, Yoshinori</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kanuma, Kosuke</au><au>Omodera, Katsunori</au><au>Nishiguchi, Mariko</au><au>Funakoshi, Takeo</au><au>Chaki, Shigeyuki</au><au>Nagase, Yasuko</au><au>Iida, Izumi</au><au>Yamaguchi, Jun-ichi</au><au>Semple, Graeme</au><au>Tran, Thuy-Anh</au><au>Sekiguchi, Yoshinori</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of 4-amino-2-cyclohexylaminoquinazolines as metabolically stable melanin-concentrating hormone receptor 1 antagonists</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2006-05-15</date><risdate>2006</risdate><volume>14</volume><issue>10</issue><spage>3307</spage><epage>3319</epage><pages>3307-3319</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>Through an optimization of the distance between two key pharmacophore features, 4-amino-2-cyclohexylaminoquinazolines were identified as potent melanin-concentrating hormone receptor 1 (MCH-R1) antagonists, leading to the discovery of ATC0065.
The optimization of the distance between two key pharmacophore features within our first hit compounds
1a and
2a led to the identification of a new class of potent non-peptidic antagonists for the MCH-R1, based around 4-amino-2-cyclohexylaminoquinazolines. In particular, ATC0065 (
2c),
N
2-[
cis-4-({2-[4-Bromo-2-(trifluoromethoxy)phenyl]ethyl}amino)cyclohexyl]-
N
4,
N
4-dimethylquinazoline-2,4-diamine dihydrochloride, bound with high affinity to the MCH-R1 (IC
50 value of 16 nM) and showed good metabolic stability in liver microsomes from human and rat.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>16434202</pmid><doi>10.1016/j.bmc.2005.12.052</doi><tpages>13</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Bioorganic & medicinal chemistry, 2006-05, Vol.14 (10), p.3307-3319 |
| issn | 0968-0896 1464-3391 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_17174200 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Animals ATC0065 Biological and medical sciences Hormones. Endocrine system Humans Lethal Dose 50 MCH-R1 antagonists Medical sciences Melanin-concentrating hormone receptor 1 antagonists Microsomes - metabolism Molecular Structure Pharmacology. Drug treatments Quinazolines - chemistry Quinazolines - pharmacology Rats Receptors, Somatostatin - antagonists & inhibitors Receptors, Somatostatin - chemistry |
| title | Identification of 4-amino-2-cyclohexylaminoquinazolines as metabolically stable melanin-concentrating hormone receptor 1 antagonists |
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