Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400 Biberach an der Riβ, Germany.
Mol Metab. 2023 Aug;74:101765. doi: 10.1016/j.molmet.2023.101765. Epub 2023 Jun 28.
Obesity is a major global health problem which can be targeted with new mechanistic diverse pharmacological interventions. Here we evaluate a new long-acting secretin receptor agonist as a potential treatment for obesity.
BI-3434 was designed as a secretin analog with stabilized peptide backbone and attached fatty acid-based half-life extension group. The peptide was evaluated in vitro for its ability to stimulate cAMP accumulation in a cell line stably expressing recombinant secretin receptor. On the functional level, stimulation of lipolysis in primary adipocytes after treatment with BI-3434 was determined. The ability of BI-3434 to activate secretin receptor in vivo was assessed in a cAMP reporter CRE-Luc mouse model. Furthermore, a diet-induced obesity mouse model was used to test the effects of BI-3434 on body weight and food intake following repeated daily subcutaneous administration alone and in combination with a GLP-1R agonist.
BI-3434 potently activated human secretin receptor. However, lipolysis was only weakly induced in primary murine adipocytes. BI-3434 had an extended half-life compared to endogenous secretin and activated target tissues like pancreas, adipose tissue, and stomach in vivo. BI-3434 did not lower food intake in lean or diet-induced obese mice, but it increased energy expenditure after daily administration. This led to a loss of fat mass, which did not translate in a significant effect on body weight. However, treatment in combination with a GLP-1R agonist led to a synergistic effect on body weight loss.
BI-3434 is a highly potent and selective agonist of secretin receptor with an extended pharmacokinetic (PK) profile. Increased energy expenditure after daily treatment with BI-3434 suggests that secretin receptor is involved in metabolic regulation and energy homeostasis. Targeting secretin receptor alone may not be an efficient anti-obesity treatment, but could be combined with anorectic principles like GLP-1R agonists.
肥胖是一个全球性的主要健康问题，可以通过新的机制多样化的药理干预来靶向治疗。在这里，我们评估一种新的长效促胰液素受体激动剂作为肥胖的潜在治疗方法。
BI-3434 被设计为一种促胰液素类似物，具有稳定的肽骨架和附着的脂肪酸半衰期延长基团。该肽在表达重组促胰液素受体的细胞系中评估其刺激 cAMP 积累的能力。在功能水平上，测定 BI-3434 处理后原代脂肪细胞中脂肪分解的情况。BI-3434 在 cAMP 报告 CRE-Luc 小鼠模型中激活促胰液素受体的能力。此外，使用饮食诱导肥胖小鼠模型测试 BI-3434 重复皮下给药对体重和食物摄入的影响，单独和与 GLP-1R 激动剂联合使用。
BI-3434 可有效激活人促胰液素受体。然而，在原代鼠脂肪细胞中仅弱诱导脂肪分解。与内源性促胰液素相比，BI-3434 具有延长的半衰期，并在体内激活靶组织如胰腺、脂肪组织和胃。BI-3434 不降低瘦鼠或饮食诱导肥胖鼠的食物摄入，但每日给药后增加能量消耗。这导致脂肪量减少，但对体重没有显著影响。然而，与 GLP-1R 激动剂联合治疗可协同降低体重。
BI-3434 是一种高效和选择性的促胰液素受体激动剂，具有延长的药代动力学（PK）特征。每日给予 BI-3434 后能量消耗增加表明促胰液素受体参与代谢调节和能量平衡。单独靶向促胰液素受体可能不是一种有效的抗肥胖治疗方法，但可以与 GLP-1R 激动剂等厌食原则结合使用。
