Drugs in Clinical Pipeline: ARRY-403

ARRY-403 [(1S)-1-[5-({3-[(2-methylpyridin-3-yl)oxy]-5-(pyridin-2-ylsulfanyl)pyridin-2-yl}amino)-1,2,4-thiadiazol-3-yl]ethane-1,2-diol] is an orally available allosteric glucokinase (GK) activator developed for the treatment of type 2 diabetes mellitus (T2DM). ARRY-403 has many favorable physicochemical characteristics (log P less than 5, molecular weight less than 500, fewer than five hydrogen bond donors, fewer than 10 hydrogen bond acceptors, high permeability) and ADME properties (low potential to cause drug–drug interactions (DDIs), a weak substrate of P-glycoprotein (P-gp), clearance by direct glucuronidation and CYP3A-mediated oxidative metabolism, data on file), but exhibits pH-dependent solubility and concentration-dependent plasma protein binding in vitro. Less than dose-proportional exposure of ARRY-403 was observed during single ascending dose studies in humans [1]. ARRY-403 holds promise for superior efficacy to other oral anti-hyperglycemic agents based on its ability to control postprandial and non-fasted blood glucose, as well as fasting blood glucose. Once a day oral therapy is predicted to provide 24-hour glycemic control in patients with mild to severe diabetes [1].

ARRY-403 potently activates human glucokinase (GK) in vitro (EC₅₀ = 79 nM at 5 mM glucose), with an S_0.5 = 0.93 mM glucose (ARRY-403 at 5 mM) and V_max = 134% compared to the no activator control. It possesses good in vitro drug-like properties (aqueous solubility, cell permeability, low potential for drug-drug interactions, low predicted hepatic clearance), and selectivity against broad panels of receptors and enzymes. 

Binding studies reveal that when ARRY-403 binds to GK, a conformational change causes both its affinity for glucose and maximal velocity to increase. Moreover, preclinical studies predicts it to be effective in “hard-to-treat” T2DM population, without contraindication or dose adjustment in patients with kidney disease or risk factors for congestive heart failure [2]. Importantly for cardiovascular safety, ARRY-403 did not cause any increases in body weight, plasma triglycerides, or plasma total cholesterol, whether used as monotherapy or in combination. The candidate demonstrated an excellent preclinical safety profile, in both in vitro selectivity assays as well as in in vivo toxicology studies including cardiovascular safety.

The activity of ARRY-403 is as follows:

EC₅₀ (GK activation assay @ 5 mM glucose) = 79 nM

Common Name: ARRY-403

Synonyms: ARRY-403; ARRY 403; ARRY 403; AMG-151; AMG 151; AMG151

IUPAC Name: (1S)-1-[5-({3-[(2-methylpyridin-3-yl)oxy]-5-(pyridin-2-ylsulfanyl)pyridin-2-yl}amino)-1,2,4-thiadiazol-3-yl]ethane-1,2-diol

CAS Number: 

Mechanism of Action: Kinase Activator; Glucokinase Activator

Indication: Treatment of Type 2 Diabetes Mellitus; Treatment of T2DM

Development Stage: Phase II

Company: Array BioPharma/Amgen

Glucokinase (GK) is an enzyme that, among other things, facilitates phosphorylation of glucose to glucose-6-phosphate. In vertebrates, GK-mediated phosphorylation generally occurs in cells in the liver, pancreas, gut, and brain. In each of these organs, GK can play a role in regulating carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising and/or falling levels of blood-glucose. Small-molecule GK activators are useful in treating type 2 diabetes because they can enhance the rate of glucose phosphorylation, and thereby reduce the amount of glucose in the blood. Therefore, GK activators lower the body's demand for insulin, especially following intake of food. In this way, GK activators provide an alternate treatment option for type 2 diabetics who otherwise may have difficulty achieving effective glycemic control. Various GK activators are known.

Glucokinase activators (GKAs) represent a promising new class of drugs for the treatment of type 2 diabetes that act directly on both the pancreas and the liver. Glucokinase (GK) is a key enzyme in glucose-sensing tissues that regulates glucose homeostatasis. GKAs lower glucose levels by enhancing the ability of pancreatic beta cells to “sense glucose” and increase insulin secretion in a glucose-dependent manner. Simultaneously, GKAs increase the uptake and disposal of glucose in the liver, while simultaneously reducing the amount it produces.

In multiple well-established in vivo models of type 2 diabetes, ARRY-403 was highly efficacious in controlling both fasting and postprandial blood glucose, with rapid onset of effect and maximal efficacy within five to eight days of once-daily dosing. Of note, ARRY-403 did not induce hypoglycemia in these diabetic animal studies. ARRY-403 was combined with existing standard-of-care drugs such as metformin, sitagliptin (a DPP-4 inhibitor), or pioglitazone (a PPARγ agonist) for additional glucose control. Importantly for cardiovascular safety, ARRY-403 did not cause any increases in body weight, plasma triglycerides, or plasma total cholesterol, whether used as monotherapy or in combination. The drug demonstrated an excellent preclinical safety profile, in both in vitro selectivity assays as well as in in vivo toxicology studies including cardiovascular safety [3].

References:

1. Chung, J.; et. al. Utilizing physiologically based pharmacokinetic modeling to inform formulation and clinical development for a compound with pH-dependent solubility. J Pharm Sci 2015, 104(4), 1522-1532.

2. Boyd, S. A.; et. al. ARRY-403, A Novel Glucokinase Activator with Potent Glucose-Dependent AntiHyperglycemic Activity in Animal Models of Type 2 Diabetes Mellitus. Poster 126-Keystone Symposium: Type 2 Diabetes and Insulin Resistance (J3), Jan 20-25, 2009, Banff, AB.
3. Boyd, S. A.; et. al. Drug Pipeline. Drug Discovery and Development Oct 2009.

Egg Consumption And Risk Of Type-2 Diabetes: For Good Results Eat 4 Eggs/week

Egg Consumption And Risk Of Type-2 Diabetes: For Good Results Eat 4 Eggs/week

Eggs are delicious but also a major source of cholesterol. High cholesterol in human has been associated with elevated blood glucose and an increased risk of Type-2 Diabetes Mellitus (T2DM). Hence, high consumption of eggs was always felt against the good health of a person.

Contrary to the above belief, the researchers from the University of Eastern Finland has given all of us a pleasant surprise with their finding showed that eggs could reduce the risk developing Type 2 diabetes by 40 %. Though they are also amazed to see the result of the study but they think the constituents of an egg improves the metabolism in the body to make use of sugar and reduce reasons that can cause diabetes.

The study involved 2332 men aged 42-60 years in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischemic Heart Disease Risk Factor Study in Eastern Finland. Dietary intakes were assessed with 4 day food records at baseline. Incident T2DM was assessed by self-administered questionnaires; by fasting and 2-hour oral-glucose-tolerance-test blood glucose measurement at re-examination rounds 4, 11, and 20 year after baseline; and by record linkage to a hospital discharge registry and reimbursement register of diabetes medication expenses. Cox proportional hazards regression analyses were used to estimate associations with the risk of incident T2DM.

The results are:

1. Eggs, if taken in right amount could reduce the risk developing Type 2 diabetes by 40% per cent.

2. Men those who regularly took 4 eggs a week were 38% less likely to fall ill than those who never ate eggs or rarely consumed them.

3. 38% of men also showed lower blood sugar levels with no increase in their cholesterol levels.

4. The study did not consider the way the egg was cooked for the study. Hence, proving that the cholesterol effect was not much among those who ate it four times in a week.

5. The associations between cholesterol intake and risk of T2DM, plasma glucose, serum insulin, and C-reactive protein were mainly nonsignificant, especially after accounting for egg consumption.

6. The results suggest an inverse association with fasting plasma glucose and serum C-reactive protein but not with serum insulin.

Article Citation: Virtanen, J. K.; et. al. Egg consumption and risk of incident type 2 diabetes in men: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr 2015 DOI: 10.3945/ajcn.114.104109

Drugs in Clinical Pipeline: PF-04937319

PF-04937319 [N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl) benzofuran-4-yl)oxy) pyrimidine-2-carboxamide] is an orally available activator of glucokinase (GCK) which is under trials in patients with Type 2 Diabetes Mellitus (T2DM).

Glucokinase is unique among the members of the hexokinase family given its low substrate affinity (K_m nearly 8 mM), positive substrate cooperativity and lack of product inhibition. As a monomeric enzyme, glucokinase achieves this cooperativity through equilibration between multiple protein conformations. In their pioneering work, Grimsby and coworkers^a demonstrated that small molecule activators were capable of binding to glucokinase at an allosteric site 20 Å remote from the active site and influencing the enzyme’s kinetic profile by modulating both K_m for glucose (also known as S_0.5) and V_max. PF-04937319 was initially evaluated in the biochemical activation assay measuring potency (EC₅₀ = 188 ± 74 uM) as well as effects on K_m (0.10 ± 0.02) and V_max (0.87 ± 0.03). Additionally, human liver microsome (HLM) stability, passive permeability, kinetic solubility (463 uM) and dofetilide binding (0% @ 10 uM), as a surrogate for hERG inhibitory activity, were evaluated [2].

The activity of PF-04937319 is as follows:

EC₅₀ (Biochemical activation assay) = 188 ± 74 uM

Common Name: PF-04937319

Synonyms:  PF-04937319; PF04937319; PF 04937319

IUPAC Name: N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide

CAS Number: -

Mechanism of Action: Kinase Activator; Glucokinase Activator; GCK activator

Indication: Diabetes; Type II Diabetes; T2DM

Development Stage: Phase I/II

Company: Pfizer

Glucokinase is one of four members of the hexokinase family of enzymes. Its expression is limited to the major organs (such as the pancreas, liver, brain and the gastrointestinal tract) that are thought to have an integrated role in glucose sensing. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the β-cells, it results in insulin release. Studies of glucokinase-linked genetically-modified mice and mutations in humans have illustrated the important roles played by glucokinase in whole-body glucose homeostasis, and suggest that the use of pharmacological agents that augment glucokinase activity could represent a viable treatment strategy in patients with type 2 diabetes. Many glucokinase activators (GKAs) have been developed, and their ability to lower the blood glucose has been shown in several animal models of type 2 diabetes. Also, in mouse models that GKAs also have the effect of stimulating the proliferation of β-cells. However, the results of recent phase II trials have shown that GKAs lose their efficacy within several months of use, and that their use is associated with a high incidence of hypoglycemia; furthermore, patients treated with GKAs frequently developed dyslipidemia [1].

Metabolic profiling in rat, dog, and human hepatocytes revealed that PF-04937319 is metabolized via oxidative (major) and hydrolytic pathways (minor). N-Demethylation to metabolite M1 [N-methyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide] was the major metabolic fate of PF-04937319 in human (but not rat or dog) hepatocytes, and was catalyzed by CYP3A and CYP2C isoforms. Qualitative examination of circulating metabolites in humans at the 100- and 300-mg doses from a 14-day multiple dose study revealed unchanged parent drug and M1 as principal components. Examination of primary pharmacology revealed M1 was less potent as a glucokinase activator than the parent drug (compound PF-04937319: EC₅₀ = 0.17 µM; M1: EC₅₀ = 4.69 µM). Furthermore, M1 did not inhibit major human P450 enzymes (IC₅₀ greater than 30 µM), and was negative in the Salmonella Ames assay, with minimal off-target pharmacology, based on CEREP broad ligand profiling [3].

References:

1. Nakamura, A.; et. al. Present status of clinical deployment of glucokinase activators. J Diabetes Investig 2015, 6(2), 124-132.
2. Pfefferkorn, J. A.; et. al. Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl) benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus. Med Chem Commun 2011, 2, 828-839. (gives synthesis and pre-clinical activity)
3. Sharma, R.; et. al. Metabolites in safety testing assessment in early clinical development: a case study with a glucokinase activator. Drug Metab Dispos 2014, 42(11), 1926-1939.
4. ClinicalTrials.gov A Trial To Assess The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Single Doses Of PF-04937319 In Subjects With Type 2 Diabetes Mellitus. NCT01044537 (retrieved 01-05-2015)

5. ClinicalTrials.gov Study To Understand Efficacy And Safety Of Investigational Agent (PF-04937319) Compared To Approved Agent (Glimepiride) In Patients With Diabetes On Metformin. NCT01517373 (retrieved 01-05-2015)

6. ClinicalTrials.gov Phase 2 Study To Evaluate Safety And Efficacy Of Investigational Drug - PF04937319 In Patients With Type 2 Diabetes. NCT01475461 (retrieved 01-05-2015)

a: For Grimsby, J.; et. al. see Science, 2003, 301, 370.