Deshpande Anil M, Bhuniya Debnath, De Siddhartha, Dave Bhavesh, Vyavahare Vinod P, Kurhade Santosh H, Kandalkar Sachin R, Naik Keshav P, Kobal Balasaheb S, Kaduskar Rahul D, Basu Sujay, Jain Vaibhav, Patil Pratima, Chaturvedi Joshi Sandhya, Bhat Ganesh, Raje Amol A, Reddy Satyanarayana, Gundu Jayasagar, Madgula Vamsi, Tambe Suhas, Shitole Prasad, Umrani Dhananjay, Chugh Anita, Palle Venkata P, Mookhtiar Kasim A
Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
Eur J Med Chem. 2017 Jun 16;133:268-286. doi: 10.1016/j.ejmech.2017.03.042. Epub 2017 Mar 24.
Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development. Here, we report the discovery and structure-activity relationship (SAR) studies on a novel 2-phenoxy-acetamide series with the aim of identifying a liver-directed GKA. Incorporation of a carboxylic acid moiety as an active hepatocyte uptake recognizing element at appropriate position of 2-phenoxy-acetamide core led to the identification of 26, a potent GKA with predominant liver-directed pharmacokinetics in mice. Compound 26 on oral administration significantly reduced blood glucose levels during an oral glucose tolerance test (oGTT) performed in diet-induced obese (DIO) mice, while showing no sign of hypoglycemia in normal C57 mice over a 10-fold dose range, even when dosed at fasted condition. Together, these data demonstrate a liver-directed GKA has beneficial effect on glucose homeostasis with reduced risk of hypoglycemia.
葡萄糖激酶激活剂（GKAs）是治疗2型糖尿病（T2D）的新兴候选药物之一。尽管在临床试验中能有效降低血糖，但许多“作用于胰腺和肝脏”的泛葡萄糖激酶激活剂已停止临床开发，主要原因是它们有导致低血糖的潜在风险。泛葡萄糖激酶激活剂使胰腺葡萄糖激酶过度敏感，即使在血糖正常以下水平也会导致胰岛素分泌，这可能是低血糖的一个合理解释。将低血糖风险降至最低的另一种方法是使用肝脏靶向性葡萄糖激酶激活剂，据报道其在临床开发中进展顺利。在此，我们报告了对一种新型2-苯氧基-乙酰胺系列化合物的发现及构效关系（SAR）研究，目的是鉴定一种肝脏靶向性葡萄糖激酶激活剂。在2-苯氧基-乙酰胺核心结构的适当位置引入羧酸部分作为活性肝细胞摄取识别元件，从而鉴定出化合物26，它是一种在小鼠体内具有主要肝脏靶向性药代动力学的强效葡萄糖激酶激活剂。化合物26口服给药后，在饮食诱导肥胖（DIO）小鼠进行的口服葡萄糖耐量试验（oGTT）中显著降低了血糖水平，而在正常C57小鼠中，即使在禁食状态下给予10倍剂量范围内的药物，也未出现低血糖迹象。总之，这些数据表明肝脏靶向性葡萄糖激酶激活剂对葡萄糖稳态具有有益作用，且低血糖风险降低。
