Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas.
School of Pharmacy, University of Maryland Eastern Shore, Princess Anne, Maryland.
Drug Dev Res. 2020 Jun;81(4):390-401. doi: 10.1002/ddr.21636. Epub 2020 Jan 9.
Diabetes mellitus is a serious metabolic disorder affecting millions of people worldwide. Phenformin and metformin are biguanide antidiabetic agents that are conveniently synthesized in a single-step chemical reaction. Phenformin was once used to lower blood glucose levels, but later withdrawn from the market in several countries because it was frequently associated with lactic acidosis. Metformin is still a widely prescribed medication for the treatment of type 2 diabetes despite the introduction of several newer antidiabetic agents. Metformin is administered orally and has desirable pharmacokinetics. Incidence of metformin-induced lactic acidosis is serious but very rare. Imeglimin, a novel molecule being investigated by Poxel and Sumitomo Dainippon Pharma in Japan, is currently in clinical trials for the treatment of type 2 diabetes. Unlike metformin, imeglimin is a cyclic molecule containing a triazine ring. However, like metformin, imeglimin is also a basic small molecule. Imeglimin is synthesized from metformin as a precursor via a single step chemical reaction. Recent mechanism of action studies suggests that imeglimin improves mitochondria function, when given in combination with metformin it helps achieve better glycemic control in patients with type 2 diabetes. We herein describe and compare the current status, synthesis, physicochemical properties, pharmacokinetic parameters, mechanism of action, and preclinical/clinical studies of metformin and imeglimin.
糖尿病是一种严重的代谢紊乱疾病，影响着全球数百万人。苯乙双胍和二甲双胍是双胍类抗糖尿病药物，可以通过一步化学反应方便地合成。苯乙双胍曾经被用于降低血糖水平，但后来在几个国家因常与乳酸性酸中毒有关而被撤出市场。尽管有几种新型抗糖尿病药物问世，二甲双胍仍然是治疗 2 型糖尿病的广泛应用药物。二甲双胍口服给药，具有理想的药代动力学特性。二甲双胍引起的乳酸性酸中毒发生率虽严重但非常罕见。吡格列酮和住友制药在日本共同研发的新型分子伊格列净，目前正在进行治疗 2 型糖尿病的临床试验。与二甲双胍不同，伊格列净是一种含有三嗪环的环状分子。然而，与二甲双胍一样，伊格列净也是一种碱性小分子。伊格列净是由二甲双胍作为前体通过一步化学反应合成的。最近的作用机制研究表明，伊格列净可改善线粒体功能，与二甲双胍联合使用时，可帮助 2 型糖尿病患者实现更好的血糖控制。本文描述并比较了二甲双胍和伊格列净的现状、合成、理化性质、药代动力学参数、作用机制以及临床前和临床研究。
