Anil Tharappel M, Harish Chandrashekaran, Lakshmi Mudigere N, Harsha Krishnareddy, Onkaramurthy Mallappa, Sathish Kumar Venkatesh, Shree Nitya, Geetha Venkatachalaiah, Balamurali Gundalmandikal V, Gopala Aralakuppe S, Madhusudhan Reddy Bobbili, Govind Madabosse K, Anup Mammen O, Moolemath Yoganand, Venkataranganna Marikunte V, Jagannath Madanahalli R, Somesh Baggavalli P
Connexios Life Sciences Pvt Ltd, Bangalore, India.
Cardiovasc Diabetol. 2014 Jan 25;13:27. doi: 10.1186/1475-2840-13-27.
AMP activated protein kinase (AMPK) regulates the coordination of anabolic and catabolic processes and is an attractive therapeutic target for T2DM, obesity and metabolic syndrome. We report the anti-hyperglycemic and anti-hyperlipidemic effects of CNX-012-570 is an orally bioavailable small molecule (molecular weight of 530 Daltons) that directly activates AMPK in DIO and db/db animal models of diabetes.
Activity and efficacy of the compound was tested in cell based as well as cell free systems in vitro. Male C57BL/6 mice fed with high fat diet (HFD) were assigned to either vehicle or CNX-012-570 (3 mg/kg, orally once a day) for 8 weeks (n = 8). Genetically diabetic db/db mice on chow diet were dosed with vehicle control or CNX-012-570 (2.5 mg/kg, orally once a day) for 6 weeks (n = 8).
CNX-012-570 is a highly potent and orally bioavailable compound activating AMPK in both cell and cell free systems. It inhibits lipolysis (33%) and gluconeogenesis (28%) in 3T3L1 cells and rat primary hepatocytes respectively. The efficacy of the molecule was translated to both DIO and db/db animal models of diabetes. CNX-012-570 has reduced fasting blood glucose levels by 14%, body weight by 24% and fasting serum triglycerides (TG) by 24%. CNX-012-570 showed a 22% reduction in fed serum cholesterol levels and 19% increase in HDL levels.In db/db mice model, CNX-012-570 has shown 18% decrease in fed glucose and 32% decrease in fasting glucose with a 2.57% reduction in absolute HbA1c. Decrease in serum insulin and glucose AUC indicates the increased insulin sensitivity. Body weight was reduced by 13% with increased browning of adipose tissue and decreased inguinal and mesenteric fat mass. There was significant reduction in liver TG and liver total cholesterol.
CNX-012-570 has the potential to control hyperglycemia and hyperlipidemia. It also reduces body weight gain with an additional benefit of minimizing cardiovascular risks in diabetics.
AMP 激活的蛋白激酶（AMPK）调节合成代谢和分解代谢过程的协调，是 2 型糖尿病、肥胖症和代谢综合征颇具吸引力的治疗靶点。我们报告了 CNX - 012 - 570 的降血糖和降血脂作用，它是一种口服生物利用度高的小分子（分子量为 530 道尔顿），可在糖尿病的饮食诱导肥胖（DIO）和 db/db 动物模型中直接激活 AMPK。
在体外基于细胞以及无细胞系统中测试该化合物的活性和功效。将喂食高脂饮食（HFD）的雄性 C57BL/6 小鼠分为溶剂对照组或 CNX - 012 - 570 组（3mg/kg，每日口服一次），持续 8 周（n = 8）。给食用普通饲料的遗传性糖尿病 db/db 小鼠给予溶剂对照或 CNX - 012 - 570（2.5mg/kg，每日口服一次），持续 6 周（n = 8）。
CNX - 012 - 570 是一种高效且口服生物利用度高的化合物，可在细胞和无细胞系统中激活 AMPK。它分别抑制 3T3L1 细胞和大鼠原代肝细胞中的脂肪分解（33%）和糖异生（28%）。该分子的功效在糖尿病的 DIO 和 db/db 动物模型中均得到体现。CNX - 012 - 570 使空腹血糖水平降低了 14%，体重降低了 24%，空腹血清甘油三酯（TG）降低了 24%。CNX - 012 - 570 使进食后血清胆固醇水平降低了 22%，高密度脂蛋白（HDL）水平升高了 19%。在 db/db 小鼠模型中，CNX - 012 - 570 使进食后血糖降低了 18%，空腹血糖降低了 32%，糖化血红蛋白（HbA1c）绝对值降低了 2.57%。血清胰岛素和葡萄糖曲线下面积（AUC）的降低表明胰岛素敏感性增加。体重降低了 13%，脂肪组织褐变增加，腹股沟和肠系膜脂肪量减少。肝脏 TG 和肝脏总胆固醇显著降低。
CNX - 012 - 570 具有控制高血糖和高血脂的潜力。它还能减少体重增加，对降低糖尿病患者的心血管风险有额外益处。
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