Imeglimin

Imeglimin is an oral anti-diabetic drug discovered by Poxel and co-developed with Sumitomo Dainippon Pharma. In 2021, Imeglimin was approved in Japan for the treatment of type 2 diabetes (T2D).

Imeglimin (EMD 387008) is an oral glucose-lowering agent. Imeglimin improves insulin sensitivity. Imeglimin also reduces reactive oxygen species (ROS) production, increases mitochondrial DNA and improves mitochondrial function[1].

Twymeeg

Imeglimin belongs to a class of tetrahydrotriazines called “glimins” and works through a different mechanism than existing antidiabetic drugs. It is thought to protect mitochondria from oxidative stress, thereby significantly reducing blood glucose levels, restoring glucose tolerance, and improving insulin sensitivity in a high-fat, high-sucrose diet mouse model. In addition, Imeglimin increases glucose uptake in skeletal muscle and inhibits hepatic gluconeogenesis like metformin.

Synthesis of Imeglimin: Metformin hydrochloride (23.1) is treated with acetaldehyde diethyl acetal (23.2) under reflux conditions of isobutanol and catalytic acid to obtain a racemic crude product 23.3. After concentration, the crude product 23.3 is treated with triethylamine and L-(+)-tartaric acid. After crystallization, the diastereomeric pure tartrate 23.4 is obtained in two steps with a yield of 40-45%. Treatment of 23.4 with ethanolic hydrochloric acid can achieve double decomposition of the salt. After crystallization from cold EtOH, the product 23 is obtained with an enantiomeric purity of 50-55%.

[1] Vial G, et al. Imeglimin normalizes glucose tolerance and insulin sensitivity and improves mitochondrialfunction in liver of a high-fat, high-sucrose diet mice model. Diabetes. 2015 Jun;64(6):2254-64. DOI:10.2337/db14-1220
[2] Detaille D, et al. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration. Cell Death Discov. 2016 Jan 18;2:15072. DOI:10.1038/cddiscovery.2015.72