Characterization of 0839 – A tool compound for pre-clinical mode-of-action studies of amylin analogues such as cagrilintide

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-07-06 DOI:10.1016/j.lfs.2025.123845

Sanaz Gabery , Tine Glendorf , Borja Ballarin-Gonzalez , Kent Pedersen , Thomas Kruse , Kirsten Raun , Rune Ehrenreich Kuhre

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引用次数: 0

Abstract

Cagrilintide (also known as 0833) is an amylin and calcitonin receptor agonist in clinical development for weight management and type-2-diabetes in a fixed-dose combination with semaglutide. Here, we introduce 0174-0839 (0839) as a tool compound for mouse and rat in vivo and in vitro studies of amylin analogues such as cagrilintide. Structurally, 0839 shares 95 % sequence homology with 0833 and contains an identical acylation sidechain. Acute administration of 0839 and 0833 to normal weight rats' dose-dependently reduced food intake to a similar degree. Sub-chronically, 0839 and 0833 had comparable small and transient reducing effects on food intake and body weight in DIO mice, with similar additional add-on effects on top of semaglutide. In DIO rats, sub-chronic administration of 0833 and 0839 profoundly reduced food intake and body weight, and both potentiated semaglutide's effects on food intake and body weight to an equal extended. Both compounds mainly reduced body weight by fat mass reduction and equally improved metabolic parameters. Notably, 0839 is available through Novo Nordisk Compound Sharing, enabling advancement of mode-of-action studies in mice and rats whilst usage of cagrilintide and other amylin analogues in clinical development are restricted due to pharmacovigilance rules.

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0839的特性-一种用于胰淀素类似物（如cagrilintide）临床前作用模式研究的工具化合物。

Cagrilintide（也被称为0833）是一种用于体重管理和2型糖尿病的临床开发的amylin和降钙素受体激动剂。在这里，我们介绍0174-0839（0839）作为工具化合物，用于小鼠和大鼠体内和体外研究amylin类似物，如cagrilintide。在结构上，0839与0833具有95 %的序列同源性，并且含有相同的酰化侧链。在体外，0839和0833对小鼠、大鼠和人降钙素和AMY3R（亚型3受体）的效价相似。正常体重大鼠急性给药0839和0833，剂量依赖性地减少食物摄取量的程度相似。亚慢性，0839和0833对DIO小鼠的食物摄入和体重有类似的小而短暂的减少作用，在西马鲁肽的基础上有类似的附加作用。在DIO大鼠中，亚慢性给药0833和0839显著减少了食物摄入和体重，并且都将西马鲁肽对食物摄入和体重的影响增强到相同程度。这两种化合物主要通过减少脂肪量来减轻体重，并同样改善代谢参数。值得注意的是，0839可以通过诺和诺德化合物共享获得，从而在小鼠和大鼠的作用模式研究中取得进展，同时在临床开发中使用cagrilintide和其他amylin类似物，并且由于药物警戒规则而受到限制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.