Dorzagliatin

Dorzagliatin (trade name HuaTangNing) is a first-in-class small molecule oral glucokinase activator (GKA) developed by Hua Medicine for the treatment of diabetic nephropathy (DKD), type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Dorzagliatin was first approved in China in September 2022 as a monotherapy or in combination with metformin, an antidiabetic drug, for adults with type 2 diabetes.

Dorzagliatin (HMS5552), a dual-acting glucokinase (GK) activator, improves glycaemic control and pancreatic β-cell function in type 2 diabetes[1].

The mechanism of action of dolagliflozin is through the activation of glucokinase, an enzyme that plays a key role in blood sugar regulation. By increasing the activity of glucokinase, dolagliflozin helps improve blood sugar control, especially in situations where blood sugar rises after a meal.

First, ethyl 2-butynoate was subjected to base-mediated olefination of 2-chlorophenol (18.5) to afford the ester 18.6 (Figure 5.2.2). Subsequent bromination with NBS and AIBN afforded the allylic bromide 18.7. Next, L-leucine methyl ester hydrochloride (18.8) was added to the base to afford the free amine, which underwent allylation with the bromide 18.7. The acid 18.9 was generated via cyclization-condensation and hydrolysis with NaOH. EDCI and HOBt promoted the formation of the final amide bond to afford the amide 18.10, and the 1,2-diol was subjected to acid-mediated acetone deprotection to afford dogliflozin (18) on a 100 kg scale.

[1] Zhu XX, et al. Dorzagliatin (HMS5552), a novel dual-acting glucokinase activator, improves glycaemic control and pancreatic β-cell function in patients with type 2 diabetes: A 28-day treatment study using biomarker-guided patient selection. Diabetes Obes DOI:10.1111/dom.13338
[2] Wang P, et al. Effects of a Novel Glucokinase Activator, HMS5552, on Glucose Metabolism in a Rat Model of Type 2 Diabetes Mellitus. J Diabetes Res. 2017;2017:5812607. DOI:10.1155/2017/5812607