Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D₂ partial agonists
Dopamine (D₂) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D₂ parti...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-01, Vol.23 (2), p.543-547 |
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| container_end_page | 547 |
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| container_issue | 2 |
| container_start_page | 543 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 23 |
| creator | Urbanek, Rebecca A Xiong, Hui Wu, Ye Blackwell, William Steelman, Gary Rosamond, Jim Wesolowski, Steven S Campbell, James B Zhang, Minli Brockel, Becky Widzowski, Daniel V |
| description | Dopamine (D₂) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D₂ partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D₂ partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model. |
| doi_str_mv | 10.1016/j.bmcl.2012.11.023 |
| format | Article |
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Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D₂ partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D₂ partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.11.023</identifier><identifier>PMID: 23237836</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>adverse effects ; agonistic behavior ; agonists ; Animals ; Antipsychotic Agents - chemical synthesis ; Antipsychotic Agents - chemistry ; Antipsychotic Agents - pharmacology ; antipsychotics ; Benzazepines - chemical synthesis ; Benzazepines - chemistry ; Benzazepines - pharmacology ; Biological Assay ; Central nervous system ; chemistry ; Disease Models, Animal ; dopamine ; Dopamine Agonists - chemical synthesis ; Dopamine Agonists - chemistry ; Dopamine Agonists - pharmacology ; Dopamine D2 receptors ; Drug Partial Agonism ; Humans ; Inhibitory Concentration 50 ; locomotion ; Locomotor activity ; Mental disorders ; Molecular Structure ; Neuroleptics ; patients ; Protein Binding - drug effects ; Rats ; Receptors, Dopamine D2 - agonists ; Schizophrenia ; Side effects ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-01, Vol.23 (2), p.543-547</ispartof><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c275t-6d6c06c689d33f67ca6e20a7534dbec657a955c49d506247ca890f4125a8b6523</citedby><cites>FETCH-LOGICAL-c275t-6d6c06c689d33f67ca6e20a7534dbec657a955c49d506247ca890f4125a8b6523</cites></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/23237836$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Urbanek, Rebecca A</creatorcontrib><creatorcontrib>Xiong, Hui</creatorcontrib><creatorcontrib>Wu, Ye</creatorcontrib><creatorcontrib>Blackwell, William</creatorcontrib><creatorcontrib>Steelman, Gary</creatorcontrib><creatorcontrib>Rosamond, Jim</creatorcontrib><creatorcontrib>Wesolowski, Steven S</creatorcontrib><creatorcontrib>Campbell, James B</creatorcontrib><creatorcontrib>Zhang, Minli</creatorcontrib><creatorcontrib>Brockel, Becky</creatorcontrib><creatorcontrib>Widzowski, Daniel V</creatorcontrib><title>Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D₂ partial agonists</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Dopamine (D₂) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. 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One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model.</description><subject>adverse effects</subject><subject>agonistic behavior</subject><subject>agonists</subject><subject>Animals</subject><subject>Antipsychotic Agents - chemical synthesis</subject><subject>Antipsychotic Agents - chemistry</subject><subject>Antipsychotic Agents - pharmacology</subject><subject>antipsychotics</subject><subject>Benzazepines - chemical synthesis</subject><subject>Benzazepines - chemistry</subject><subject>Benzazepines - pharmacology</subject><subject>Biological Assay</subject><subject>Central nervous system</subject><subject>chemistry</subject><subject>Disease Models, Animal</subject><subject>dopamine</subject><subject>Dopamine Agonists - chemical synthesis</subject><subject>Dopamine Agonists - chemistry</subject><subject>Dopamine Agonists - pharmacology</subject><subject>Dopamine D2 receptors</subject><subject>Drug Partial Agonism</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>locomotion</subject><subject>Locomotor activity</subject><subject>Mental disorders</subject><subject>Molecular Structure</subject><subject>Neuroleptics</subject><subject>patients</subject><subject>Protein Binding - drug effects</subject><subject>Rats</subject><subject>Receptors, Dopamine D2 - agonists</subject><subject>Schizophrenia</subject><subject>Side effects</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkb1O3EAUhUdRorCQvECKZEoam_n3uEQQfiQkpGyQ0o2ux9e7s7I9jscbiS15VJ4Er5ZQU93ifOcU9yPkG2c5Z9ycbfKq820uGBc55zkT8gNZcGVUJhXTH8mClYZltlR_jshxShvGuGJKfSZHQgpZWGkWBJaP_bTGFBKFvqbL8180NhS60MdpHWAXW6TNNmFNK-x3sMMh9DiziSZs0U_hH9I6DvsC0svnpyc6wDgFaCmsYh_SlL6QTw20Cb--3hPycPXz98VNdnd_fXtxfpd5UegpM7XxzHhjy1rKxhQeDAoGhZaqrtAbXUCptVdlrZkRas5tyRrFhQZbGS3kCTk97A5j_LvFNLkuJI9tCz3GbXJcWM1sWXD7DrSQhdRW6xkVB9SPMaURGzeMoYPx0XHm9hbcxu0tuL0Fx7mbLcyl76_726rD-q3y_-0z8OMANBAdrMaQ3MNyXtCzIsm1tvIFqKaN6Q</recordid><startdate>20130115</startdate><enddate>20130115</enddate><creator>Urbanek, Rebecca A</creator><creator>Xiong, Hui</creator><creator>Wu, Ye</creator><creator>Blackwell, William</creator><creator>Steelman, Gary</creator><creator>Rosamond, Jim</creator><creator>Wesolowski, Steven S</creator><creator>Campbell, James B</creator><creator>Zhang, Minli</creator><creator>Brockel, Becky</creator><creator>Widzowski, Daniel V</creator><general>Elsevier Ltd</general><scope>FBQ</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20130115</creationdate><title>Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D₂ partial agonists</title><author>Urbanek, Rebecca A ; 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| ispartof | Bioorganic & medicinal chemistry letters, 2013-01, Vol.23 (2), p.543-547 |
| issn | 0960-894X 1464-3405 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | adverse effects agonistic behavior agonists Animals Antipsychotic Agents - chemical synthesis Antipsychotic Agents - chemistry Antipsychotic Agents - pharmacology antipsychotics Benzazepines - chemical synthesis Benzazepines - chemistry Benzazepines - pharmacology Biological Assay Central nervous system chemistry Disease Models, Animal dopamine Dopamine Agonists - chemical synthesis Dopamine Agonists - chemistry Dopamine Agonists - pharmacology Dopamine D2 receptors Drug Partial Agonism Humans Inhibitory Concentration 50 locomotion Locomotor activity Mental disorders Molecular Structure Neuroleptics patients Protein Binding - drug effects Rats Receptors, Dopamine D2 - agonists Schizophrenia Side effects Structure-Activity Relationship |
| title | Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D₂ partial agonists |
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