Gliquidone

Description

Gliquidone is a second generation sulfonylurea that selectively inhibits ATP-sensitive potassium channel currents (IK_ATP) in pancreatic β-cells (IC₅₀s = 0.45, 119.1, and 149.7 μM for HIT-T15 cells, cardiomyocytes, and vascular smooth muscle cells, respectively). It is also a peroxisome proliferator-activated receptor γ (PPARγ) agonist (EC₅₀ = 10 μM in a transactivation assay). Gliquidone (0.2 nmol/g) decreases plasma levels of D-glucose and stimulates insulin release in anesthetized rats. It decreases blood glucose levels, serum alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) activities, and hepatic lipid peroxidation and increases hepatic glutathione (GSH) levels in a rat model of diabetes induced by streptozotocin (STZ; ) when administered at a dose of 10 mg/kg.

Originator

Glurenorm,Thornae,W. Germany,1975

The Uses of Gliquidone

Gliquidone is an anti diabetic agent used in the treatment of hypoglycemia which leads to an increased risk in diabetic cardiovascular disease. Also used in the treatment diabetic nephropathy.

Background

Gliquidone is a sulfonylurea drug used to treat diabetes mellitus type 2. It is an ATP-dependent K+ (KATP) channel blocker. This block causes a depolarization which leads to activation of voltage-dependent Ca channels and Ca2+ influx, and eventually increases insulin release.

What are the applications of Application

Gliquidone is an ATP-dependent K+ (KATP) channel blocker

Indications

Used in the treatment of diabetes mellitus type 2.

Definition

ChEBI: 1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea is a member of isoquinolines.

Manufacturing Process

A mixture consisting of 4 grams of 1,2,3,4-tetrahydro-4,4-dimethyl-7- methoxy-isochromanedione-(1,3) (MP 95° to 97°C), 2.53 grams of 4- aminosulfonyl-phenyl-(2)-ethylamine and 150 ml of xylene was heated for 2 hours at its boiling point in an apparatus provided with a water separator. Thereafter, the reaction mixture was allowed to cool and was then vacuumfiltered, and the filter cake was recrystallized from n-propanol in the presence of activated charcoal. 2.9 grams (58% of theory) of 1,2,3,4-tetrahydro-4,4- dimethyl-2-[p-aminosulfonylphenyl-(2)-ethyl]-7-methoxy-isoquinolinedione- (1,3), MP 203° to 205°C, of the formula below were obtained.
32.2 grams of 1,2,3,4-tetrahydro-4,4-dimethyl-2-[p-aminosulfonylphenyl-(2)-ethyl]-7-methoxy-isoquinolinedione-(1,3) were dissolved in 700 ml of dimethylformamide, 9.1 grams of potassium tert-butylate were added to the solution, and, while cooling the mixture with ice, 14.9 grams of cyclohexyl isocyanate were added dropwise thereto.
Subsequently, the reaction mixture was stirred for 5 hours on an ice bath and was then allowed to stand overnight at -2°C. Thereafter, the reaction solution was admixed with water, the precipitate formed thereby was separated by vacuum-filtration, the filtrate was admixed with more water, and the aqueous solution was acidified with 2N hydrochloric acid. A greasy substance precipitated out which crystallized after a brief period of contact with boiling methanol. 2.6 grams (85% of theory) of 1,2,3,4-tetrahydro-2-[p-(N'- cyclohexyl-ureido-N-sulfonyl)-phenethyl]-4,4-dimethyl-7-methoxyisoquinolinedione-(1,3), MP 180° to 182°C, were obtained.

Therapeutic Function

Oral hypoglycemic

Hazard

Low toxicity by ingestion. A reproductive hazard.

Pharmacokinetics

Gliquidone is an anti-diabetic drug in the sulfonylurea class. In patients with diabetes mellitus, there is a deficiency or absence of a hormone manufactured by the pancreas called insulin. Insulin is the main hormone responsible for the control of sugar in the blood. Gliquidone is an antidiabetic medication which is used in those patients with adult maturity onset or non-insulin dependent diabetes (NIDDM). It works by lowering blood sugar levels by stimulating the production and release of insulin from the pancreas. It also promotes the movement of sugar from the blood into the cells in the body which need it.

Metabolism

Not Available

References

[1]. ocaña m, del pozo e, baeyens jm. gliquidone, an atp-dependent k+ channel antagonist, antagonizes morphine-induced hypermotility. eur j pharmacol, 1993, 239(1-3): 253-255.
[2]. ocaña m, baeyens jm. role of atp-sensitive k+ channels in antinociception induced by r-pia, an adenosine a1 receptor agonist. naunyn schmiedebergs arch pharmacol, 1994, 350(1): 57-62.
[3]. von nicolai h, brickl r, eschey h, et al. duration of action and pharmacokinetics of the oral antidiabetic drug gliquidone in patients with non-insulin-dependent (type 2) diabetes mellitus. arzneimittelforschung, 1997, 47(3): 247-252.
[4]. tuerk tr, bandur s, nuernberger j, et al. gliquidone therapy of new-onset diabetes mellitus after kidney transplantation. clin nephrol, 2008, 70(1): 26-32.