Dorzagliatin (HMS5552)

Dorzagliatin (HMS5552) is an innovative oral diabetes drug we are developing: glucokinase activator (GKA) with a novel mechanism of action, Glucokinase Activator)，It aims to repair the function of glucose sensor glucokinase (GK) in patients with type 2 diabetes，Restore blood glucose homeostasis，To achieve the purpose of treating type 2 diabetes。Huanling Pharmaceutical has the global market development rights for this product, which has been approved by the National Medical Products Administration (NMPA)。Evidence from pre-clinical to completed Phase III clinical studies of Dorzagliatin: GKA Dorzagliatin (Doglietine), first in development in China，The hypoglycemic effect was clear in phase II and III studies，Rarely hypoglycemia，Significantly improved beta cell function，It has the potential to improve GK function and blood glucose homeostasis after T2DM injury。Recent studies have shown that dorzagliatin can significantly increase the expression of GLP-1 in islet alpha cells and protect islet beta cells from another perspective。

In the development of dorzagliatin，We always focus on the effective GKA concentration，Improve GK efficiency (Vmax) at the same time，And protect the sensing function of GK (nHill)，To avoid glucose-dependent destruction of GK，Thus, it can repair blood glucose homeostasis in patients with type 2 diabetes。At the same time, Huatling Pharmaceutical supports the role of GKA in key organs such as liver, pancreas and small intestine through excellent chemical preparation technology。

Dorzagliatin is expected to become a new generation of drugs for the treatment of type 2 diabetes with a new mechanism, which can be used as a single drug to treat patients with incipient and early type 2 diabetes, and can also be used in combination with the current clinical use of anti-diabetic drugs。

Human blood glucose homeostasis is as important a physiological state as water, electrolyte, oxygen, body temperature and other homeostasis systems, and is an important energy supply system to maintain the normal operation of human nervous and immune systems。Normal blood sugar is 4-6.Fluctuation within 5mM, steady-state imbalance of blood glucose deviating from this range for a long time will induce microangiopathy, eye disease, diabetic foot and other microangiopathy, and aggravate cardiovascular and cerebrovascular and other major vascular complications。

Type 2 diabetes is a progressive disease in which people with type 2 diabetes lose their sensitivity to glucose, which is the cause of impairment of beta cell function。Impaired islet function causes blood glucose fluctuation, which leads to uncontrolled blood glucose homeostasis, aggravation of the disease and frequent complications。Impaired expression and function of glucokinase in diabetic patients lead to hyperglycemia, which is the cause of type 2 diabetes. It is also the main reason why current diabetes drugs, including insulin, cannot control the continuous development of type 2 diabetes and the continuous decline of islet function。

Like room temperature sensors, glucokinase (GK) senses changes in blood sugar in the human body, and automatically switches on glucose-raising and hypoglycemic mechanisms to maintain the normal physiological homeostasis range of human blood sugar (4-6).5 mM), is a human blood glucose homeostasis sensor, by regulating the release of glucogen-controlling hormones and glycogen synthesis to maintain blood glucose homeostasis。

Glucokinase (GK) acts as a glucose sensor，When blood sugar is too high，Glucokinase (GK) activity was increased in islet beta cells，Promote insulin secretion;Glucokinase (GK) activity was increased in hepatocytes，Promote liver glycogen synthesis;Meanwhile, glucokinase (GK) activity was enhanced in α cells，Inhibition of glucagon release，So as to achieve the purpose of lowering blood sugar。Conversely, when blood sugar is too low, the expression and activity of glucokinase (GK) decreases, causing blood sugar to rise to the physiological target range。In this way, glucokinase (GK), as a glucose sensor, maintains the body's blood glucose homeostasis and controls the blood glucose level within the target range。

In addition, maintaining blood glucose homeostasis requires the joint involvement of glucokinase (GK), which is distributed in multiple organs, to play the core role of glucokinase (GK) as a glucose sensor。

It has been found that decreased expression or activity of glucokinase (GK) is common in T2DM patients。 The "sensor" cannot properly sense and transmit glucose levels, and the body cannot properly secrete glucose-controlling hormones, blood glucose homeostasis can not be maintained, and glucose metabolism is disrupted. Therefore, a new strategy for diabetes treatment to restore the function and activity of glucokinase (GK) is glucokinase activator (GKA).。

The pharmacological basis of glucokinase activators (GKA) has been disclosed since 2001，Research on GKA is booming，More than 100 GKA patents have been published to date，More than 20 GKA drugs have entered clinical studies，One of the most advanced is Warneck's dorzagliatin，Approved for listing。