Boc5 的传奇仍在继续，这是首个具有体内活性的非肽类胰高血糖素样肽-1 受体激动剂。
A continued saga of Boc5, the first non-peptidic glucagon-like peptide-1 receptor agonist with in vivo activities.
机构信息
National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
出版信息
Acta Pharmacol Sin. 2012 Feb;33(2):148-54. doi: 10.1038/aps.2011.169.
Abstract
Glucagon-like peptide-1 (GLP-1)-based therapy presents a promising option for treating type 2 diabetes. However, there are several limitations relative to the peptidic GLP-1 mimetics currently on the market or under development. This concern has led to a continued interest in the search for non-peptidic agonists for GLP-1 receptor (GLP-1R). Here, we briefly review the discovery, characterization and current status of a novel class of cyclobutane-derivative-based non-peptidic agonists for GLP-1R, including Boc5 and its newly discovered analogue WB4-24. Although the oral bioavailability of such compounds still poses great challenges, the progress made so far encourages us to identify a truly 'druggable' small molecule agonist for GLP-1R.
摘要
胰高血糖素样肽-1（GLP-1）类药物为治疗 2 型糖尿病提供了一种很有前景的选择。然而，目前市场上或正在开发的肽类 GLP-1 类似物存在一些局限性。这种担忧促使人们持续关注寻找非肽类 GLP-1 受体（GLP-1R）激动剂。在这里，我们简要回顾了一类新型基于环丁烷衍生物的非肽类 GLP-1R 激动剂的发现、特性和现状，包括 Boc5 及其新发现的类似物 WB4-24。尽管这类化合物的口服生物利用度仍然存在很大的挑战，但迄今为止取得的进展鼓励我们鉴定出真正可成药的 GLP-1R 小分子激动剂。
相似文献
1
A continued saga of Boc5, the first non-peptidic glucagon-like peptide-1 receptor agonist with in vivo activities.Boc5 的传奇仍在继续，这是首个具有体内活性的非肽类胰高血糖素样肽-1 受体激动剂。
Acta Pharmacol Sin. 2012 Feb;33(2):148-54. doi: 10.1038/aps.2011.169.
2
Non-peptidic glucose-like peptide-1 receptor agonists: aftermath of a serendipitous discovery.非肽类葡萄糖类似物胰高血糖素样肽-1 受体激动剂：偶然发现的后续。
Acta Pharmacol Sin. 2010 Sep;31(9):1026-30. doi: 10.1038/aps.2010.107. Epub 2010 Aug 2.
3
Reversal of obesity and insulin resistance by a non-peptidic glucagon-like peptide-1 receptor agonist in diet-induced obese mice.非肽类胰高血糖素样肽-1 受体激动剂在饮食诱导肥胖小鼠中逆转肥胖和胰岛素抵抗。
PLoS One. 2010 Dec 3;5(12):e14205. doi: 10.1371/journal.pone.0014205.
4
Structural basis of peptidomimetic agonism revealed by small- molecule GLP-1R agonists Boc5 and WB4-24.小分子 GLP-1R 激动剂 Boc5 和 WB4-24 表现出的肽模拟激动作用的结构基础。
Proc Natl Acad Sci U S A. 2022 May 17;119(20):e2200155119. doi: 10.1073/pnas.2200155119. Epub 2022 May 13.
5
Molecular modeling of the three-dimensional structure of GLP-1R and its interactions with several agonists.胰高血糖素样肽-1受体（GLP-1R）三维结构及其与多种激动剂相互作用的分子模拟
J Mol Model. 2009 Jan;15(1):53-65. doi: 10.1007/s00894-008-0372-2. Epub 2008 Oct 22.
6
Boc5, a non-peptidic glucagon-like Peptide-1 receptor agonist, invokes sustained glycemic control and weight loss in diabetic mice.Boc5是一种非肽类胰高血糖素样肽-1受体激动剂，可使糖尿病小鼠的血糖得到持续控制并减轻体重。
PLoS One. 2008 Aug 6;3(8):e2892. doi: 10.1371/journal.pone.0002892.
7
A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice.一种对糖尿病db/db小鼠有效的胰高血糖素样肽1受体非肽类激动剂。
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):943-8. doi: 10.1073/pnas.0610173104. Epub 2007 Jan 9.
8
Discovery of a potent and long-acting Xenopus GLP-1-based GLP-1/glucagon/Y receptor triple agonist.发现一种强效且长效的基于 Xenopus GLP-1 的 GLP-1/胰高血糖素/Y 受体三重激动剂。
Eur J Med Chem. 2023 Feb 5;247:115036. doi: 10.1016/j.ejmech.2022.115036. Epub 2022 Dec 21.
9
Stapled, Long-Acting Xenopus GLP-1-Based Dual GLP-1/Glucagon Receptor Agonists with Potent Therapeutic Efficacy for Metabolic Disease.基于 Xenopus GLP-1 的长效订书钉状双重 GLP-1/胰高血糖素受体激动剂，具有治疗代谢疾病的强大疗效。
Mol Pharm. 2021 Aug 2;18(8):2906-2923. doi: 10.1021/acs.molpharmaceut.0c00995. Epub 2021 Jul 9.
10
Cinchonine, a Potential Oral Small-Molecule Glucagon-Like Peptide-1 Receptor Agonist, Lowers Blood Glucose and Ameliorates Non-Alcoholic Steatohepatitis.金雀花堿，一种有潜力的口服小分子胰高血糖素样肽-1 受体激动剂，可降低血糖并改善非酒精性脂肪性肝炎。
Drug Des Devel Ther. 2023 May 11;17:1417-1432. doi: 10.2147/DDDT.S404055. eCollection 2023.
引用本文的文献
1
Synthesis of Bis(amino acids) Containing the Styryl-cyclobutane Core by Photosensitized [2+2]-Cross-cycloaddition of Allylidene-5(4)-oxazolones.通过光敏[2+2]-环加成反应合成含苯乙烯-环丁烷核的双（氨基酸）。
Int J Mol Sci. 2023 Apr 20;24(8):7583. doi: 10.3390/ijms24087583.
2
Structural basis of peptidomimetic agonism revealed by small- molecule GLP-1R agonists Boc5 and WB4-24.小分子 GLP-1R 激动剂 Boc5 和 WB4-24 表现出的肽模拟激动作用的结构基础。
Proc Natl Acad Sci U S A. 2022 May 17;119(20):e2200155119. doi: 10.1073/pnas.2200155119. Epub 2022 May 13.
3
Stereoselective, Ruthenium-Photocatalyzed Synthesis of 1,2-Diaminotruxinic Bis-amino Acids from 4-Arylidene-5(4)-oxazolones.手性、钌光催化的 4-芳亚甲基-5(4)-噁唑啉酮合成 1,2-二氨基三亚甲基双氨基酸。
J Org Chem. 2022 Mar 4;87(5):3529-3545. doi: 10.1021/acs.joc.1c03092. Epub 2022 Feb 10.
4
A quinoxaline-based compound ameliorates bone loss in ovariectomized mice.基于喹喔啉的化合物可改善去卵巢小鼠的骨丢失。
Exp Biol Med (Maywood). 2021 Dec;246(23):2502-2510. doi: 10.1177/15353702211032133. Epub 2021 Jul 25.
5
DeepCPI: A Deep Learning-based Framework for Large-scale in silico Drug Screening.DeepCPI：一种基于深度学习的大规模计算机药物筛选框架。
Genomics Proteomics Bioinformatics. 2019 Oct;17(5):478-495. doi: 10.1016/j.gpb.2019.04.003. Epub 2020 Feb 6.
6
Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes.胰高血糖素样肽-1及其B类G蛋白偶联受体：通往治疗成功的漫长征程。
Pharmacol Rev. 2016 Oct;68(4):954-1013. doi: 10.1124/pr.115.011395.
7
Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors.B类G蛋白偶联受体激活中细胞外结构域的差异需求
J Biol Chem. 2016 Jul 15;291(29):15119-30. doi: 10.1074/jbc.M116.726620. Epub 2016 May 13.
8
Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure.G蛋白偶联受体（GPCR）胰高血糖素亚家族的里程碑式研究：从小分子调节剂到晶体结构
Acta Pharmacol Sin. 2015 Sep;36(9):1033-42. doi: 10.1038/aps.2015.78. Epub 2015 Aug 17.
9
The non-peptide GLP-1 receptor agonist WB4-24 blocks inflammatory nociception by stimulating β-endorphin release from spinal microglia.非肽类胰高血糖素样肽-1受体激动剂WB4-24通过刺激脊髓小胶质细胞释放β-内啡肽来阻断炎性伤害性感受。
Br J Pharmacol. 2015 Jan;172(1):64-79. doi: 10.1111/bph.12895. Epub 2014 Nov 24.
10
Clinical application of glucagon-like Peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus.胰高血糖素样肽-1 受体激动剂在 2 型糖尿病治疗中的临床应用。
Endocrinol Metab (Seoul). 2013 Dec;28(4):262-74. doi: 10.3803/EnM.2013.28.4.262.
本文引用的文献
1
Cyclobutane derivatives as novel nonpeptidic small molecule agonists of glucagon-like peptide-1 receptor.作为新型非肽小分子胰高血糖素样肽-1 受体激动剂的环丁烷衍生物。
J Med Chem. 2012 Jan 12;55(1):250-67. doi: 10.1021/jm201150j. Epub 2011 Dec 8.
2
Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4.外周和中枢 GLP-1 受体群体介导了外周给予的 GLP-1 受体激动剂利拉鲁肽和 exendin-4 的厌食作用。
Endocrinology. 2011 Aug;152(8):3103-12. doi: 10.1210/en.2011-0174. Epub 2011 Jun 21.
3
Third intracellular loop of glucagon like-peptide-1 receptor is coupled with endogenous mono-ADP-ribosyltransferase - novel type of receptor regulation?胰高血糖素样肽-1 受体的第三细胞内环与内源性单 ADP-核糖基转移酶偶联 - 新型受体调节？
Eur J Pharmacol. 2011 Sep;666(1-3):35-42. doi: 10.1016/j.ejphar.2011.05.033. Epub 2011 May 27.
4
Reversal of obesity and insulin resistance by a non-peptidic glucagon-like peptide-1 receptor agonist in diet-induced obese mice.非肽类胰高血糖素样肽-1 受体激动剂在饮食诱导肥胖小鼠中逆转肥胖和胰岛素抵抗。
PLoS One. 2010 Dec 3;5(12):e14205. doi: 10.1371/journal.pone.0014205.
5
Novel small molecule glucagon-like peptide-1 receptor agonist stimulates insulin secretion in rodents and from human islets.新型小分子胰高血糖素样肽-1 受体激动剂可刺激啮齿动物和人胰岛的胰岛素分泌。
Diabetes. 2010 Dec;59(12):3099-107. doi: 10.2337/db10-0689. Epub 2010 Sep 7.
6
Non-peptidic glucose-like peptide-1 receptor agonists: aftermath of a serendipitous discovery.非肽类葡萄糖类似物胰高血糖素样肽-1 受体激动剂：偶然发现的后续。
Acta Pharmacol Sin. 2010 Sep;31(9):1026-30. doi: 10.1038/aps.2010.107. Epub 2010 Aug 2.
7
Effects of exendin-4 alone and with peptide YY(3-36) on food intake and body weight in diet-induced obese rats.单独使用 exendin-4 以及与肽 YY(3-36) 联合使用对饮食诱导肥胖大鼠的摄食量和体重的影响。
Obesity (Silver Spring). 2011 Jan;19(1):121-7. doi: 10.1038/oby.2010.136. Epub 2010 Jun 17.
8
Incretin-based therapies for type 2 diabetes mellitus: current status and future prospects.基于肠降血糖素的 2 型糖尿病治疗药物：现状与展望。
Pharmacotherapy. 2010 Jun;30(6):609-24. doi: 10.1592/phco.30.6.609.
9
Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor.胰高血糖素样肽-1 与胰高血糖素样肽-1 受体胞外结构域复合物的晶体结构
J Biol Chem. 2010 Jan 1;285(1):723-30. doi: 10.1074/jbc.M109.033829. Epub 2009 Oct 27.
10
Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control?胰高血糖素样肽-1 的新兴心血管作用：除血糖控制之外的潜在治疗益处？
Br J Pharmacol. 2009 Aug;157(8):1340-51. doi: 10.1111/j.1476-5381.2009.00376.x.
Zotero 插件