Structure-Activity Relationship and Biological Investigation of SR18292 (16), a Suppressor of Glucagon-Induced Glucose Production.
Structure-Activity Relationship and Biological Investigation of SR18292 (16), a Suppressor of Glucagon-Induced Glucose Production.
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DOI：
10.1021/acs.jmedchem.0c01450
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发表时间：
2021-01-28
影响因子：
7.3
通讯作者：
Kamenecka TM
中科院分区：
文献类型：
--
作者：
Lin H;Sharabi K;Lin L;Ruiz C;Zhu D;Cameron MD;Novick SJ;Griffin PR;Puigserver P;Kamenecka TM
尽管治疗2型糖尿病(T2D)的药物疗法多种多样，但在实现血糖控制方面仍存在挑战。几种新的降糖策略目前正在进行临床研究，强调了更强有力的治疗方法的必要性。此前，我们已经证明，用小分子(SR18292，16)抑制PGC1DNA活性可以减少肝细胞释放葡萄糖，改善糖尿病小鼠模型的高血糖。尽管16种β阻滞剂在结构上与已知的β阻滞剂相似，但这里描述的详细的合成孔径雷达研究已经导致识别出缺乏β肾上腺素能活性的类似物，这些类似物仍然保持抑制高血糖素诱导的肝细胞释放葡萄糖的能力，并改善糖尿病小鼠模型的高血糖。因此，这些化合物以一种不包括肾上腺素能信号的机制发挥其生物学效应。这些探针分子可能导致一种新的治疗方法来治疗T2D，无论是作为单一药物还是联合治疗。
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 PGC1α 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 SAR studies described herein have led to the identification of analogs 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.
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影响因子：
29
作者：
Lin HV;Accili D
通讯作者：
Accili D
影响因子：
64.8
作者：
Rodgers, JT;Lerin, C;Puigserver, P
通讯作者：
Puigserver, P
影响因子：
16
作者：
Dominy, John E., Jr.;Lee, Yoonjin;Jedrychowski, Mark P.;Chim, Helen;Jurczak, Michael J.;Camporez, Joao Paulo;Ruan, Hai-Bin;Feldman, Jessica;Pierce, Kerry;Mostoslavsky, Raul;Denu, John M.;Clish, Clary B.;Yang, Xiaoyong;Shulman, Gerald I.;Gygi, Steven P.;Puigserver, Pere
通讯作者：
Puigserver, Pere
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
10.6
作者：
Sharabi K;Tavares CD;Rines AK;Puigserver P
通讯作者：
Puigserver P