A gk activator has the promise of potentially affecting. In the pancreatic betacell, glucokinase is a key regulator enzyme. Targeting hepatic glucokinase to treat diabetes with ttp399. The glucosephosphorylating enzyme glucokinase has structural, kinetic, and molecular genetic features that are ideal for its primary role as glucose sensor in a network of neuroendocrine sentinel cells that maintain glucose homeostasis in many vertebrates including humans. Glucokinase activators can lower glucose levels in both animal and human type 2 diabetes, but their mechanism of action has never been explored in humans. Optimization led to the identification of 33 as a compound that displayed activity in an oral. If you previously purchased this article, log in to readcube. Nonalcoholic fatty liver disease concerns with glucokinase. Glucokinase activity is not generally inducible, however, in the livers of adult ruminant animals because not enough glucose normally escapes degradation by ruminal microflora.
Abstract of efficacy and safety of glucokinase activators. Glucokinase gk plays a critical role for maintaining glucose. M, respectively, for the recombinant enzymes, which translates into cellular systems ec50s 1. Apr 17, 2009 guided by this fundamental knowledge, several glucokinase activators are now being developed, and have so far been shown to lower blood glucose in several animal models of type 2 diabetes and in. Jul 18, 2003 glucokinase gk plays a key role in wholebody glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic.
Assessing the potential of glucokinase activators in. Tmg123, a novel glucokinase activator, exerts durable. All gkas increase the binding affinity for glucose. Glucokinase activators gkas are being developed for the treatment of type 2 diabetes. Present status of clinical deployment of glucokinase. Although the introduction of a new class of glucoselowering drugs with a different mode of action is always welcome, particularly in this era of. Psn010, glucokinase and diabetes potential health benefits on diabetes and research finds 2007. Ttp355 a glucokinase activator glucokinase gk is an enzyme glucokinase gk is an enzyme localized primarily in pancreatic. Phosphorylation of glucose by glucokinase in the liver promotes glycogen synthesis, while in the.
Investigation of functionally liver selective glucokinase. In the liver, glucokinase mediates gluconeogenesis, glucose utilization and glycogen synthesis. A glucokinase activator and a sulfonylurea might be coprescribed to synergize treatment success for type 2 diabetes t2d. Effects of a novel glucokinase activator, hms5552, on glucose.
Targeting hepatic glucokinase to treat diabetes with. Glucokinase gk plays a critical role in the control of wholebody glucose homeostasis. Identification of a new class of glucokinase activators. Pharmacokinetic and pharmacodynamic drug interaction study of. The glucosephosphorylating enzyme glucokinase gk was identified as an outstanding drug target for developing antidiabetic medicines because it has an exceptionally high impact on glucose homeostasis because of its glucose sensor role in pancreatic bcells and as a ratecontrolling enzyme for hepatic glucose clearance and glycogen synthesis. Exploring the in vivo mechanisms of action of glucokinase. This article is from cardiovascular diabetology, volume. Glucokinase gk plays a key role in wholebody glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic. Apr 22, 2011 more on gka action at the molecular, cellular, organ, and wholebody levels. Pdf present status of clinical deployment of glucokinase.
Glucokinase activators for diabetes therapy scienceopen. Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10. Because many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, compounds that can activate gk may serve as effective treatments for type 2 diabetes. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates.
The preceding discussion on the molecular biochemistry of gk and of the gk system in health and disease should leave no doubt that pharmacological activation of this enzyme has a high potential for the treatment of type 2 diabetes. To test this hypothesis, we evaluated a hepatoselective glucokinase activator, pf04991532, in gotokakizaki rats. Glucokinase in beta cells serves as a glucose sensor, amplifying insulin secretion as blood glucose rises. Pharmacokinetic and pharmacodynamic drug interaction study. It couples insulin secretion in the pancreas with plasma glucose concentration, and improves glucose utilization in the liver, thus affecting two. Efficacy and safety of glucokinase activators for type 2 diabetes mellitus. Glucokinase gk plays a critical role for maintaining glucose homeostasis with regulating glucose uptake in liver and insulin secretion in pancreas. Pharmaceutical interventions for diabetes aim to control glycaemia and to. A method for treating diabetes and related disease employing the compound, enantiomer, prodrug, diastereomer, or salt is also provided. Glucokinase is inducible, so that enzyme activation and enzyme synthesis can meet the acute and chronic needs for more glucose phosphorylation. On the other hand, the gk activity can be elevated by glucokinase activators gkas, which bind to the allosteric site of gk and contribute to govern blood glucose by enhancing glucose uptake in. Small molecule glucokinase activators gkas represent a new strategy to treat type 2 diabetes. Glucokinase have a single allosteric site where the glucoseregulating protein gkrp binds in the nucleus of the cell in its inactive form when there is a low concentration of glucose present in the cell. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can allosterically activate gk may address this issue.
Enzyme activators are molecules that bind to enzymes and increase their activity. The lens serves almost all the patents and scholarly work in the world as a free, open and secure digital public good, with user privacy a paramount focus. Piragliatin ro4389620, a novel glucokinase activator. Type 2 diabetes is characterized by elevated blood glucose levels resulting from a pancreatic. Glucokinase gk has a major role in the control of blood glucose homeostasis and is a strong potential target for the pharmacological treatment of type 2 diabetes. If untreated, diabetic complications develop that cause loss of vision, peripheral neuropathy, impaired kidney function, heart disease, and stroke. Compounds that directly activate glucokinase effectively reduce blood sugar in patients with diabetes but increase the risk of adverse hypoglycemic events. Design, synthesis and sar of novel glucokinase activators. Glucokinase gk activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. Increased hepatic glucose output, the primary liver dysregulation associated with type 2 diabetes mellitus t2dm, is not directly or effectively targeted by the currently available classes of glucoselowering medications except metformin. Download fulltext pdf download fulltext pdf download fulltext pdf glucokinase activators for diabetes therapy article pdf available in diabetes care 34 suppl 2supplement 2. Processes of their preparation are also described in the disclosure. To improve the effectiveness of the treatment while minimizing adverse reactions such as hypoglycemia, vella et al.
A compound, enantiomer, prodrug, diastereomer, or salt is provided which is an activator of the enzyme glucokinase and thus is believed to be useful in as treating diabetes and related diseases, which compound has the structure i. Discovery of 2pyridyl ureas as glucokinase activators. Glucokinase gk primarily exerts its effect through modulatory actions in the pancreatic. Gk activators have been reported to decrease blood glucose levels in patients with type 2 diabetes mellitus. Aug 14, 2012 although glucokinase activators gkas have been proposed as a promising therapy for the potential treatment of diabetes, it has yet to be confirmed that the same small molecule activators modulate glucokinase activity simultaneously in liver, pancreas and brain. Recent updates on glucokinase activators for the treatment of type 2 diabetes mellitus. View enhanced pdf access article on wiley online library html view download pdf for offline viewing. We evaluated the insulinotropic and antihyperglycaemic actions of glucokinase activators gkas, especially through acute and subchronic. Assessing the potential of glucokinase activators in diabetes. Several glucokinase activators gkas are presently at various stages of clinical development. These molecules are often involved in the allosteric regulation of enzymes in the control of metabolism.
The present invention further provides for pharmaceutical compositions comprising the same as well as methods of treating, preventing, delaying the time to onset or reducing the risk for the. Mar 20, 2017 on the other hand, the gk activity can be elevated by glucokinase activators gkas, which bind to the allosteric site of gk and contribute to govern blood glucose by enhancing glucose uptake in. Importance of glucokinase in regulating the blood glucose. The renantiomer was a potent activator with an ec 50 of 0. Nov 10, 2014 importance of glucokinase in regulating the blood glucose. Glucokinase gk is the enzyme responsible for the conversion of glucose to glucose6phosphate, and it functions as a key regulator of glucose homeostasis. Activators of glucokinase increase the sensitivity of the enzyme to glucose, leading to increased. Azd1656 glucokinase activator hexokinase 4 metabolism. Glucokinase is a key enzyme in glucose homeostasis and acts in the liver and pancreas. The relationship of glucokinase activatorinduced hypoglycemia. Compounds of the present disclosure are 2,2,2trisubstituted acetamide derivatives of formula i, its polymorphs, stereoisomers, prodrugs, solvates, pharmaceutically acceptable salts and formulations thereof, useful as glucokinase activator.
Current gkas have diverse chemical structures but are small molecules able to bind to an allosteric site stabilizing a highaffinity conformation of the enzyme. Effect of exogenously administered glucagon versus spontaneous endogenous counterregulation on glycaemic recovery from insulininduced hypoglycaemia in patients with type 2 diabetes treated with a novel glucokinase activator, azd1656, and metformin. Glucokinase activators gkas offer a promising new opportunity for the treatment of t2dm patients. Male spraguedawley sd rats were divided into four groups. This unmet need might be addressed through activation of a specific enzymemember of the hexokinase family, namely glucokinase. Apr 20, 2017 differences between hexokinase and glucokinase april 20, 2017 by dr hamza arshad 17 comments hexokinase or glucokinase is an enzyme that convert glucose to glucose 6 phosphate. Opposite effects of a glucokinase activator and metformin on. Glucokinase activators have been demonstrated to be effective in enhancing. Glucokinase activators for diabetes therapy diabetes care.
Here we describe our medicinal chemistry campaign to improve o. Property based optimisation of glucokinase activators. A gk activator has the promise of potentially affecting both the. Glucokinase activators offer a potentially promising. Us20190233449a1 glucokinase activators and methods of using.
An example of an enzyme activator working in this way is fructose 2,6bisphosphate, which activates phosphofructokinase 1 and increases the rate of. Identification of mangiferin as a potential glucokinase. Glucokinase activators as new type 2 diabetes therapeutic. The disclosure also describes method to characterize partial. Glucokinase activators gkas in diabetes management. Herein we sought to evaluate whether liver specific pharmacological activation of hepatic glucokinase is an effective strategy to reduce hyperglycemia without causing adverse hepatic lipids changes. The hepatoselective glucokinase activator pf04991532.
Although the introduction of a new class of glucoselowering drugs with a different mode of action is always welcome, particularly in. Stimulation of hepatocyte glucose metabolism by novel small. Herein we report the identification and initial optimization of a novel series of allosteric glucokinase activators gkas. Recent advances in glucokinase activators for the treatment of type 2 diabetes. The disclosure of pharmacological glucokinase activator gka development in 2001 was followed by the release of almost 100 patents. However, clinical development of gk activators has failed due to the loss of glucoselowering effects and. The present invention further provides for pharmaceutical compositions comprising the same as well as methods of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which one or more glucokinase activator is indicated, including type 1 and 2 diabetes, impaired.
Even if glucokinase activators such as dorzagliatin succeed in being commercialised, their positioning among the armamentarium of medications already available for the treatment of type 2 diabetes will depend on comparative efficacy and safety profiles, ease of use especially with twice daily administration, and cost. Azd1656 is a potent, selective 100fold versus hexokinase 1 and 2 and a pharmacology screening panel, activator of human and rat glucokinase in vitro. Thus, the enhanced pd effect warrants further investigation to define the optimal dose combination between glucokinase activators and sulfonylureas with regard to efficacy. Pdf recent advances in glucokinase activators for the treatment of. Several gkas were remarkably effective in lowering blood glucose during early.
We report here the mechanism of action of two novel and potent direct activators of gk. Activators of glucokinase increase the sensitivity of the. We describe a class of antidiabetic agents that act as nonessential, mixedtype gk activators gkas that increase the glucose affinity and maximum velocity v max of gk. Pdf glucokinase is a member of the hexokinase family of enzymes that are responsible for the. In humans, the glucokinase gene gck is located on chromosome 7p15. Glucokinase gka activators activatorsinducers, agonists. The objective of the study was to investigate the effects of the glucokinase activator piragliatin ro4389620 on. Although glucokinase is a known therapeutic target in type 2 diabetes, previous attempts to activate it have not been clinically successful because of side effects and limited efficacy. Ttp355 a glucokinase activator american diabetes association. Stimulation of hepatocyte glucose metabolism by novel.
Us20190233449a1 glucokinase activators and methods of. Psn010, a member of glucokinase activators, is designed to lower blood glucose levels by increasing glucose uptake in the liver and helping the pancreas secrete more insulin. Pdf glucokinase activators for diabetes therapy researchgate. Aug 01, 2019 glucokinase activators have been demonstrated to be effective in enhancing. The present invention provides for novel compounds of formulas i and ii and pharmaceutically acceptable salts and cocrystals thereof which have glucokinsae activator activity. Recent advances in glucokinase activators for the treatment. Opposite effects of a glucokinase activator and metformin. Activators of glucokinase increase the sensitivity of the enzyme to glucose, leading to increased insulin secretion and liver glycogen synthesis and a decrease in liver glucose output. Pdf recent advances in glucokinase activators for the. Effects of a novel glucokinase activator, hms5552, on. New hope for glucokinase activators in type 2 diabetes. To investigate the pharmacokinetics and pharmacodynamics of a dual. Glucokinase is very important in the regulation of insulin secretion and has been known as the pancreatic betacell sensor. Guided by this fundamental knowledge, several glucokinase activators are now being developed, and have so far been shown to lower blood glucose in several animal models of type 2 diabetes and in.
This clinical pharmacology study was designed to investigate the potential glucose. Glucokinase plays a central role in glucose homeostasis and small molecule activators of the glucokinase enzyme have been the subject of significant pharmaceutical research in the quest for agents capable of delivering improved glycaemic control. Jan 16, 2019 although glucokinase is a known therapeutic target in type 2 diabetes, previous attempts to activate it have not been clinically successful because of side effects and limited efficacy. Allosteric activation of human glucokinase diginole. Present status of clinical deployment of glucokinase activators. We investigated the possible effects of a novel glucokinase activator gka, hms5552, to the gk in rats with type 2 diabetes mellitus t2dm. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in. Differences between hexokinase and glucokinase april 20, 2017 by dr hamza arshad 17 comments hexokinase or glucokinase is an enzyme that convert glucose to. Herein we report the identification and initial optimization of a novel series of glucokinase activators gkas. Glucokinase activator the art of process chemistry. Small molecule activators of glucokinase gkas have been explored extensively as potential anti. Due to this, glucokinase and glucokinase activators are the focus of treatment for those with type 2 diabetes mellitus. Now, researchers from amgen have identified compounds that act via a glucokinase regulator, opening the door to a potentially safer strategy to modulate hepatic glucokinase activity.752 1093 1154 1426 693 962 100 540 242 1451 675 1564 1396 216 879 883 1186 1163 1135 925 1584 937 243 62 11 1389 1495 1562 1403 445 1442 256 1366 1215 747 623 313 891 910 476 294 1023 725 520