Pdf recent advances in glucokinase activators for the. An allosteric activator of glucokinase impairs the. This application relates to novel urea glucokinase activators and use of the compounds of the invention for preparation of a medicament for the treatment of various diseases, e. Design and synthesis of acetylenyl benzamide derivatives. The glucosephosphorylating enzyme glucokinase gk was. Regulatory t cell migration is dependent on glucokinase. Present status of clinical deployment of glucokinase activators.
Both of these enzymes are iso enzymes, which means that both of them have the same chemical natures and have same action but have different physical properties and site of action etc. Due to a recent breakthrough leading to the identification of a novel class of small molecules termed glucokinase activators, the old enzyme became a new target in diabetes therapy. The r enantiomer, ro281675, was a potent gka, whereas the s enantiomer, ro281674, was inactive fig. Mk0941 free base is an orally active glucokinase activator, with ec 50 s of 240 and 65 nm for recombinant human glucokinase in the presence of 2. 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. Novel, highly potent systemic glucokinase activators for the. We hypothesized that the hepatic lipidosis was due to the structurebased toxicity and later established that it was due to the formation of. Glucokinase activity in the pancreas is critical in enhancing insulin release in response to hyperglycaemia. Apr 20, 2017 hexokinase or glucokinase is an enzyme that convert glucose to glucose 6 phosphate. Lead optimization of an acetylenyl benzamide series led to the discovery of several active compounds via in vitro enzyme assays ec50 glucokinase activators for the potential treatment of type 2 diabetes volume. Coghlan, and loranne agius2 glucokinase gk has a major role in the control of.
New hope for glucokinase activators in type 2 diabetes. Glucokinase, on the other hand, is primarily a liver enzyme, but is also found on the inner plasma membrane of pancreatic. 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. Researcharticle effects of a novel glucokinase activator, hms5552, on glucose metabolism in a rat model of type 2 diabetes mellitus pingwang,1 huililiu,2 lichen,3. Glucokinase activators offer a potentially promising. Glucokinase inhibitors agonists modulators antagonists. Gk activators are the new class of drug candidates which design, synthesis and antidiabetic activity of novel sulfamoyl benzamide derivatives as glucokinase activators. Glucokinase activators gkas in diabetes management.
Due to this, glucokinase and glucokinase activators are the focus of treatment for those with type 2 diabetes mellitus. Modulation of glucokinase by glucose, smallmolecule. Gk acts as a glucose sensor and elicits glucose specific responses from the respective cell types, e. Stimulation of hepatocyte glucose metabolism by novel. Arry403, a glucokinase activator with potent glucosedependent antihyperglycemic activity in animal models of type 2 diabetes mellitus. The medium was renewed and 74 kbqml1 du14c glucose plus vehicle or compound 0. Efficacy and safety of glucokinase activators for type 2 diabetes mellitus.
Antidiabetic agents, type 2 diabetes, allosteric activator, glucokinase activators abstract. Glucokinase activators gkas promise a new pharmacotherapy for diabetics. Pdf glucokinase activators for diabetes therapy researchgate. In the pancreatic betacell, glucokinase is a key regulator enzyme. Glucokinase gk plays a critical role for maintaining glucose homeostasis. Discovery of piragliatinfirst glucokinase activator.
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. We identified a small molecule gk activator, compound a, that increased the glucose affinity and maximal velocity v max of gk. Glucokinase is very important in the regulation of insulin secretion and has been known as the pancreatic betacell sensor. Ttp355 a glucokinase activator american diabetes association. Therefore, very little free glucose is normally absorbed by the ruminant intestinal tract to induce this hepatic enzyme. The role of glucokinase as a glucose sensor is due for the development of novel glucokinase activators as its allosteric properties. Glucokinase gk catalyses the formation of glucose 6phosphate from glucose and atp.
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. Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Human gk isoform 3 cocrystals that belonged to the p6522 space group were generated with numerous gk activators in the presence of glucose in hanging drop trays in 100mm hepes ph 7. Smallmolecule gkas gk activators modulate gk catalytic activity and glucose affinity and are currently being pursued as a treatment for type 2 diabetes. Glucokinase activators gkas promise a new pharmacotherapy for diabetics franz m matschinsky1 and daniel porte jr2,3 addresses. Identification of mangiferin as a potential glucokinase. Mar 20, 2017 the natural product mangiferin compound 7 has been identified as a potential glucokinase activator by structurebased virtual ligand screening. Mice had free access to water and food throughout the study period. The hepatoselective glucokinase activator pf04991532. Glucokinase activators with improved physicochemicalproperties and off target effects american chemical society national meeting and exposition kirman lc, schuster hf, grondine ms et al 2010 240th august 22 medi197 investigation of functionally liver selective glucokinase activators american chemical society national meeting and exposition. Targeting hepatic glucokinase to treat diabetes with ttp399, a hepatoselective glucokinase activator adrian vella1, jennifer l.
Crystal structure determination of human glucokinase in complex with 16a. Glucokinase gka activators activatorsinducers, agonists. Buse3, carmen valcarce2 the therapeutic success of interventions targeting glucokinase gk activation for the treatment of type 2. Targeting hepatic glucokinase to treat diabetes with ttp399. Glucokinase is a key enzyme in glucose homeostasis and acts in the liver and pancreas. 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. Molecular basis for the role of glucokinase regulatory. Stimulation of hepatocyte glucose metabolism by novel small. Pdf design, synthesis and antidiabetic activity of novel. Allosteric activation of human glucokinase diginole. What is the difference between hexokinase and glucokinase. 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.
Apr 22, 2011 the network of glucokinaseexpressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Protective effects of glucokinase activator on the onset. Glucokinase gk, also called hexokinase iv, plays an essential role in blood glucose homeostasis, catalyzing glucose phos phorylation that is the ratelimiting reaction for glycolysis. The renantiomer was a potent activator with an ec 50 of 0.
A novel glucokinase activator ro4389620 improved fasting and postprandial plasma glucose in type 2 diabetic. Gk is a monomeric enzyme that catalyzes the atpdependent phosphorylation of dglucose to dglucose6phosphate, which is the initial, as well as ratelimiting step, in cellular glucose uptake and metabolism. Recent updates on glucokinase activators and glucokinase regulatory protein disrupters for the treatment of type 2 diabetes mellitus authors. Diabetes copyright 2019 targeting hepatic glucokinase to. The most recent study of a glucokinase activator is that of dorzagliatin, administered in increasing doses to 258 people with t2d over a 12. Pfizers pf 04937319 glucokinase activators for the.
Assessing the potential of glucokinase activators in. Us 20090054444 a1 substituted phenylacetamides and their. 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 for diabetes therapy scienceopen. Metabolic and vascular department, roche, nutley, nj 07110, usa. Ttp399, a liver selective glucokinase activator gka that. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy. Jun 18, 20 glucokinase gk is a monomeric allosteric enzyme and plays a pivotal role in blood glucose homeostasis. Gk is an emerging target for the therapeutic management of t2d patients as it plays a key function in the regulation of carbohydrate breakdown. Gujral punjab technical university, jalandhar kapurthala highway, kapurthala, punjab, grimt, raduar, yamuna nagar, haryana. This is the expression of a fourth hexokinase isoenzyme. Type 2 diabetes is characterized by elevated blood glucose levels resulting from a pancreatic. Stimulation of hepatocyte glucose metabolism by novel small molecule glucokinase activators katy j. Unlike hexokinase, glucokinase is not inhibited by its product, glc6p, yet its activity is stimulated by insulin and inhibited by diabetogenic hormones e.
We determined the crystal structure of xenopus gk and gkrp. The activity of glucokinase ex a new treatment for diabetes. Mk0941 free base exhibits strong glucoselowering activity and is a potential therapeutic agent for treatment of type 2 diabetes. Discovery of piragliatinfirst glucokinase activator studied. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the. Pdf on may 1, 2011, franz m matschinsky and others published. Tmg123, a novel glucokinase activator, exerts durable. The network of glucokinaseexpressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy.
Kishore and colleagues demonstrate that treg cell migration requires the activation of glycolysis by the enzyme glucokinase induced via a treg cellselective pi3kmtorc2 pathway. All of the hexokinases can mediate phosphorylation of glucose to glucose6phosphate g6p, which is the first step of both glycogen synthesis and glycolysis. For instance, in a 9day study in obob mice, a glucokinase activator improved the overall glucose profile while showing comparable antihyperglycemic effects in oral glucose tolerance tests at the beginning and end of the study. Glucokinase gk plays a key role in the control of blood glucose homeostasis. Gk progress curves monitoring product formation are linear up to 1 mm glucose, but biphasic at 5 mm, with the transition. Hexokinase or glucokinase is an enzyme that convert glucose to glucose 6 phosphate. Regulatory t cell localization to inflammatory sites is key to their homeostatic function. Glucokinase activators for diabetes therapy may 2010 status report franz m. Glucokinase activator lowers blood glucose concentrations by enhancing glucose uptake in the liver and increasing insulin production by the pancreatic.
Here we describe the research and development of a process for the practical synthesis of glucokinase activator r1 as a potential drug for treating type2 diabetes. The future for glucokinase activation is looking brighter after fresh data on vtvs oral adjunct to insulin therapy in type 1 diabetes. Ttp355 a glucokinase activator glucokinase gk is an enzyme glucokinase gk is an enzyme localized primarily in pancreatic. Hepatocytes were incubated further for 3 h at 37c, then washed three times in icecold pbs, and. Glucokinase in beta cells serves as a glucose sensor, amplifying insulin secretion as blood glucose rises. Results this article discusses an overview of t2dm, biology of gk, role of gk in t2dm. Glucokinase gk activation as a potential strategy to treat type 2 diabetes t2d is well recognized.
Recent updates on glucokinase activators and glucokinase regulatory protein disrupters for the treatment of type 2 diabetes mellitus volume. This enzyme which convert glucose to glucose 6 phosphate exists in two isomer forms. Glucokinase activators for the potential treatment of type 2. Aug 14, 2012 several glucokinase activators gkas are presently at various stages of clinical development. The natural product mangiferin compound 7 has been identified as a potential glucokinase activator by structurebased virtual ligand screening. Targeting hepatic glucokinase to treat diabetes with. Its expression is limited to the major organs such as the pancreas, liver, brain and the gastrointestinal tract that are thought. Assessing the potential of glucokinase activators in diabetes. We report here the mechanism of action of two novel and potent direct activators of gk. Since pf04991532 is a selective liver activator, we were able to evaluate the effect of exclusively hepatic glucokinase activation. Several glucokinase activators gkas are presently at various stages of clinical development. 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. Glucokinase gk is a hexokinase isozyme, related homologously to at least three other hexokinases.
To improve the effectiveness of the treatment while minimizing adverse reactions such as hypoglycemia, vella et al. Pdf recent advances in glucokinase activators for the treatment of. Research paper predictive blood glucose lowering efficacy by glucokinase activators in high fat fed female zucker rats gj coope1, am atkinson1, c allott1, d mckerrecher1, c johnstone1, kg pike1, pc holme2, h vertigan1, d gill1, mp coghlan1 and b leighton1 1cardiovascular and gastrointestinal department, astrazeneca, macclesfield, cheshire, uk and 2syngenta central toxicology. Compound a augmented insulin secretion from isolated rat islets and enhanced glucose utilization in primary cultured rat hepatocytes. Recent updates on glucokinase activators for the treatment of type 2 diabetes mellitus. 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. Histological analysis showed that genetic activation of glucokinase in the. Apr 17, 2009 the dosedependent effect of glucokinase activators gkas of high, medium and low potency on glucokinase activity and glucose homeostasis are illustrated by a modelling experiment using. Pdf glucokinase is a member of the hexokinase family of enzymes that are. The glycolytic pathway is characterized in some cell types 8 10, in pancreatic beta cells 4, 11 and alpha cells, hepatocytes 15 19, certain specific pituitary cells, and brain neurons by a specific feature. 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. Vanderkooi, phd 1 ali naji, phd, md 3 ramakanth sarabu, phd 4 joseph grimsby, phd 4 t ype 2 diabetes is characterized by elevated blood glucose levels result. Glucokinase activators for diabetes therapy europe pmc. In humans, the glucokinase gene gck is located on chromosome 7p15.
Azd1656 glucokinase activator hexokinase 4 metabolism. Other glucokinase activators have produced conflicting results as to whether activation of glucokinase can produce efficacious glucose control without impacting hepatic lipid burden. 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. Ro281675 also reversed the inhibitory action of the human glucokinase regulatory protein gkrp 14 fig. Gujral punjab technical university, jalandhar kapurthala highway, kapurthala, punjab, india manish kaushik. A fresh view of glycolysis and glucokinase regulation. Atherogenic, fibrotic and glucose utilising actions of. Nov 10, 2014 importance of glucokinase in regulating the blood glucose. Glucokinase is one of four members of the hexokinase family of enzymes. New phase ii data bolster vtv therapeutics glucokinase activator aspirations scrip. Akita mice were also challenged with diet containing 0. Overall, the available data suggests that potent glucokinase activators with the desired effects on the kinetic properties of the enzyme can be designed to achieve strong and persistent antidiabetic effects. Present status of clinical deployment of glucokinase activators ncbi.
After 10 days acclimation, diabetic mice were randomly divided into there. One atp molecule is cleaved to adp and the phosphate released is added to glucose. Role of glucokinase in regulation of physiological insulin secretion from pancreatic beta cells. Smallmolecule glucokinase activators have been identified that bind to an allosteric site of the enzyme and increase its catalytic activity, thus offering a novel approach to the treatment of type 2 diabetes. Glucokinase gk, hexokinase iv plays a unique role in glucose homeostasis. Gk glucokinase is an enzyme central to glucose metabolism that displays positive cooperativity to substrate glucose. Glucokinase activators gkas are novel agents for diabetes which act by enhancing the formation of glucose6phosphate leading to increased insulin. Present status of clinical deployment of glucokinase. Vanderkooi, phd 1 ali naji, phd, md 3 ramakanth sarabu, phd 4 joseph grimsby, phd 4 t ype 2 diabetes is characterized by elevated blood glucose levels resulting from a. Gk is regulated by gk regulatory protein gkrp, and indirectly by allosteric effectors of gkrp. Body weight gain, serum cholesterol levels, serum triglyceride levels and serum free fatty acid levels showed no. The network of glucokinaseexpressing cells in glucose. In the liver, glucokinase mediates gluconeogenesis, glucose utilization and glycogen synthesis. The search for innovative and clinicallydifferentiated medicines for.
Activation of gk was exquisitely sensitive to the chirality of the molecule. Glucokinase is ex pressed in a variety of tissues including liver hepatocytes and pancreatic. A specific feature of gk amongst hexokinases is that it can cycle between active and inactive conformations as a function of glucose concentration, resulting in a unique positive kinetic cooperativity with glucose, which turns gk into a unique key sensor of glucose metabolism, notably in the pancreas. Glucokinase and the potential of glucokinase activation in. Effects of a novel glucokinase activator, hms5552, on. Us 2041711 a1 urea glucokinase activators the lens. Identification of mangiferin as a potential glucokinase activator by. If untreated, diabetic complications develop that cause loss of vision, peripheral neuropathy, impaired kidney function, heart disease, and stroke. Novel acetylenylcontaining benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucokinase activity stimulated by 10 mm glucose concentration and glucose uptake in rat hepatocytes. Recent updates on glucokinase activators and glucokinase.
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