AZD1656

Mechanism of action: Glucokinase (GK; hexokinase 4) activator


Preclinical pharmacology

AZD1656 is a potent, selective (>100-fold versus hexokinase 1 and 2 and a pharmacology screening panel), activator of human and rat glucokinase in vitro; EC50’s = 0.057 and 0.072μM, respectively, for the recombinant enzymes, which translates into cellular systems (EC50’s = 1.39 and 0.47μM in human and rat hepatocytes, respectively). AZD1656 reduces plasma glucose levels in a dose-dependent fashion, with a rapid onset of action, in normo-glycaemic insulin resistant rats and diabetic mice, when dosed acutely and when dosed once daily for up to 28 days.


Safety and tolerability

AZD1656 has been studied in single doses of up to 180 mg and multiple doses to 150 mg BID for 8 days in healthy volunteers as well as alone and in combination with other blood glucose control agents in diabetic patients at 200 mg daily for up to 6 months duration. In both healthy volunteers and diabetic patients no significant clinical effects other than glucose lowering were noted.

Preclinical studies of up to 12 month duration have been performed.  These revealed a potent glucose lowering effect, and thereby, the results of chronic toxicology studies in healthy animals were confounded by severe hypoglycaemia at higher doses and sequalae such as Wallerian type nerve degeneration and skeletal muscle fibre degeneration.  Additional changes, also considered secondary to hypoglycaemia, were seen in the liver (loss of hepatocellular glycogen).


Clinical pharmacology

In a Phase 2 study in Japanese type 2 diabetic subjects, AZD1656, given BID at high (40-200mg/day), medium (20-140mg/day) and low (10-80mg/day) doses over a 4 month period, has been found to lower HbA1c and fasting plasma blood (FPG) glucose levels with a 50mg dose producing compound levels of ~2 x EC50 in plasma.  However, this effect was transient trending towards pre-dose levels between weeks 8 and 16 and there was no statistically significant change in either HbA1c or FPG from baseline at 4 months.


Suitable for and exclusions

Preclinical reprotoxicology data are available and have not identified any specific risks. Women of child-bearing potential using highly effective contraception can be included.

Proposed indications should be evaluated against the risk of hypoglycaemia in non-diabetic subjects.

Additional Information


Clinical trials for this compound

See all of the clinical trials currently associated with this compound:


Publications for this compound

Find out more about this compound by reading related publications:

PubMed.gov

Recent updates on glucokinase activators for the treatment of type 2 diabetes mellitus

Effect of exogenously administered glucagon versus spontaneous endogenous counter-regulation on glycaemic recovery from insulin-induced hypoglycaemia in patients with type 2 diabetes treated with a novel glucokinase activator, AZD1656, and metformin

Chronic glucokinase activator treatment at clinically translatable exposures gives durable glucose lowering in two animal models of type 2 diabetes

The novel use of a heterozygous knockout mouse for embryofetal development assessment of a glucokinase activator

Dose-ranging study with the glucokinase activator AZD1656 as monotherapy in Japanese patients with type 2 diabetes mellitus

Dose-ranging study with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus on metformin

Tolerability, pharmacokinetics, and pharmacodynamics of the glucokinase activator AZD1656, after single ascending doses in healthy subjects during euglycemic clamp

Safety, pharmacokinetics and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656 in patients with type 2 diabetes mellitus

Glucokinase activators AZD6370 and AZD1656 do not affect the central counterregulatory response to hypoglycemia in healthy males


Gene information from the NCBi

This compound works on the following genes: