Structure–Activity Relationship and Biological Investigation of SR18292 (16), a Suppressor of Glucagon-Induced Glucose Production,Journal of Medicinal Chemistry

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Structure–Activity Relationship and Biological Investigation of SR18292 (16), a Suppressor of Glucagon-Induced Glucose Production
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-01-12 , DOI: 10.1021/acs.jmedchem.0c01450
Hua Lin _{1,

2} , Kfir Sharabi _{3,

4} , Li Lin ₁ , Claudia Ruiz ₁ , Di Zhu ₁ , Michael D Cameron ₁ , Scott J Novick ₁ , Patrick R Griffin ₁ , Pere Puigserver _{3,

4} , Theodore M Kamenecka ₁

Affiliation

Despite a myriad of available pharmacotherapies for the treatment of type 2 diabetes (T2D), challenges still exist in achieving glycemic control. Several novel glucose-lowering strategies are currently under clinical investigation, highlighting the need for more robust treatments. Previously, we have shown that suppressing peroxisome proliferator-activated receptor gamma coactivator 1-alpha activity with a small molecule (SR18292, 16) can reduce glucose release from hepatocytes and ameliorate hyperglycemia in diabetic mouse models. Despite structural similarities in 16 to known β-blockers, detailed structure–activity relationship studies described herein have led to the identification of analogues lacking β-adrenergic activity that still maintain the ability to suppress glucagon-induced glucose release from hepatocytes and ameliorate hyperglycemia in diabetic mouse models. Hence, these compounds exert their biological effects in a mechanism that does not include adrenergic signaling. These probe molecules may lead to a new therapeutic approach to treat T2D either as a single agent or in combination therapy.

中文翻译：

SR18292 的构效关系和生物学研究 (16)，一种胰高血糖素诱导的葡萄糖生成抑制剂

尽管有无数可用的药物疗法可用于治疗 2 型糖尿病 (T2D)，但在实现血糖控制方面仍然存在挑战。目前正在对几种新型降糖策略进行临床研究，强调需要更强大的治疗方法。以前，我们已经表明，用小分子 (SR18292, 16 ) 抑制过氧化物酶体增殖物激活受体 γ 共激活因子 1-α 活性可以减少肝细胞的葡萄糖释放并改善糖尿病小鼠模型中的高血糖症。尽管16的结构相似对于已知的 β 受体阻滞剂，本文描述的详细结构-活性关系研究已经导致鉴定出缺乏 β 肾上腺素能活性的类似物，这些类似物仍然保持抑制胰高血糖素诱导的肝细胞葡萄糖释放和改善糖尿病小鼠模型中的高血糖症的能力。因此，这些化合物在不包括肾上腺素能信号传导的机制中发挥其生物学作用。这些探针分子可能会导致一种新的治疗方法，将 T2D 作为单一药物或联合疗法进行治疗。

更新日期：2021-01-28

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