Krista Jaunsleine , Linda Supe , Jana Spura , Sten van Beek , Anna Sandström , Jessica Olsen , Carina Halleskog , Tore Bengtsson , Ilga Mutule , Benjamin Pelcman
{"title":"用于刺激葡萄糖摄取的新型β2-肾上腺素受体激动剂的开发-环胺的手性和环大小的重要性。","authors":"Krista Jaunsleine , Linda Supe , Jana Spura , Sten van Beek , Anna Sandström , Jessica Olsen , Carina Halleskog , Tore Bengtsson , Ilga Mutule , Benjamin Pelcman","doi":"10.1016/j.bmcl.2023.129562","DOIUrl":null,"url":null,"abstract":"<div><p>β<sub>2</sub>-Adrenergic receptor (β<sub>2</sub><span><span><span>AR) agonists have been reported to stimulate glucose uptake (GU) by </span>skeletal muscle cells<span> and are therefore highly interesting as a possible treatment for </span></span>type 2 diabetes<span> (T2D). The chirality of compounds often has a great impact on the activity of β</span></span><sub>2</sub>AR agonists, although this has thus far not been investigated for GU. Here we report the GU for a selection of synthesized acyclic and cyclic β-hydroxy-3-fluorophenethylamines. For the <em>N</em>-butyl and the <em>N</em>-(2-pentyl) compounds, the (<em>R</em>) and (<em>R,R</em>) <strong>(3d</strong> and <strong>7e</strong><span>) stereoisomers induced the highest GU. When the compounds contained a saturated nitrogen containing 4- to 7-membered heterocycle, the (</span><em>R,R,R</em><span><span>) enantiomer of the </span>azetidine (</span><strong>8a</strong><span>) and the pyrrolidine (</span><strong>9a</strong>) had the highest activity. Altogether, these results provide pivotal information for designing novel β<sub>2</sub>AR agonist for the treatment of T2D.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"97 ","pages":"Article 129562"},"PeriodicalIF":2.2000,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Development of novel β2-adrenergic receptor agonists for the stimulation of glucose uptake – The importance of chirality and ring size of cyclic amines\",\"authors\":\"Krista Jaunsleine , Linda Supe , Jana Spura , Sten van Beek , Anna Sandström , Jessica Olsen , Carina Halleskog , Tore Bengtsson , Ilga Mutule , Benjamin Pelcman\",\"doi\":\"10.1016/j.bmcl.2023.129562\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>β<sub>2</sub>-Adrenergic receptor (β<sub>2</sub><span><span><span>AR) agonists have been reported to stimulate glucose uptake (GU) by </span>skeletal muscle cells<span> and are therefore highly interesting as a possible treatment for </span></span>type 2 diabetes<span> (T2D). The chirality of compounds often has a great impact on the activity of β</span></span><sub>2</sub>AR agonists, although this has thus far not been investigated for GU. Here we report the GU for a selection of synthesized acyclic and cyclic β-hydroxy-3-fluorophenethylamines. For the <em>N</em>-butyl and the <em>N</em>-(2-pentyl) compounds, the (<em>R</em>) and (<em>R,R</em>) <strong>(3d</strong> and <strong>7e</strong><span>) stereoisomers induced the highest GU. When the compounds contained a saturated nitrogen containing 4- to 7-membered heterocycle, the (</span><em>R,R,R</em><span><span>) enantiomer of the </span>azetidine (</span><strong>8a</strong><span>) and the pyrrolidine (</span><strong>9a</strong>) had the highest activity. Altogether, these results provide pivotal information for designing novel β<sub>2</sub>AR agonist for the treatment of T2D.</p></div>\",\"PeriodicalId\":256,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry Letters\",\"volume\":\"97 \",\"pages\":\"Article 129562\"},\"PeriodicalIF\":2.2000,\"publicationDate\":\"2023-11-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0960894X23004407\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X23004407","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Development of novel β2-adrenergic receptor agonists for the stimulation of glucose uptake – The importance of chirality and ring size of cyclic amines
β2-Adrenergic receptor (β2AR) agonists have been reported to stimulate glucose uptake (GU) by skeletal muscle cells and are therefore highly interesting as a possible treatment for type 2 diabetes (T2D). The chirality of compounds often has a great impact on the activity of β2AR agonists, although this has thus far not been investigated for GU. Here we report the GU for a selection of synthesized acyclic and cyclic β-hydroxy-3-fluorophenethylamines. For the N-butyl and the N-(2-pentyl) compounds, the (R) and (R,R) (3d and 7e) stereoisomers induced the highest GU. When the compounds contained a saturated nitrogen containing 4- to 7-membered heterocycle, the (R,R,R) enantiomer of the azetidine (8a) and the pyrrolidine (9a) had the highest activity. Altogether, these results provide pivotal information for designing novel β2AR agonist for the treatment of T2D.
期刊介绍：
Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.
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