NZ502434A - Aminoguanidine for treating niddm - Google Patents

Abstract

Disclosed is the use of a protein glycation inhibitor, or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of Type II diabetes. The protein glycation inhibitor may be selected from aminoguanidine and it's derivatives or analogues, hydrazine type compounds and hydrazine derivatives, thiosemicarbazides, derivatives of pyridine N-oxide and crosslink breakers such as phenacylthiazolium bromide and it's derivatives or analogues.

Description

502434 F3 ' <r*\ - " NEW ZEALAND PATENTS ACT, 1953 Divided out of No: 3-2^835 Dated: 18 December 1996 COMPLETE SPECIFICATION AMINOGUANIDINE FOR TREATING NIDDM We, SMITHKLINE BEECHAM, PLC, a British company of New Horizons Court, Brentford, Middlesex TW8 OEP, United Kingdom, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page 1 a) INTELLECTUAL PROPERfrOFICEl ni.. iz 2 0 JAM 2000 I RECEIVED AMINOGUANIDINE FOR TREATING NIDDM This invention relates to a novel method for the treatment of and/or prophylaxis of non-insulin dependant (NIDDM or Type II) diabetes, and in particular to the use of an inhibitor of protein gh cation, such as aminoguanidine, for the said treatment and/or prophylaxis.

Hydrazmecarboximidamide (hereinafter 'aminoguanidine') is a known compound (Journal of American Chemical Society, 57, 2730, (1935)).

Aminoguanidine is known to be an NO synthase inhibitor (Eur. J Pharmacol., 233, 119- 125).

Aminoguanidine is also known to be an inhibitor of protein glycation and such activity is considered to be closely linked to the activity of aminoguanidine in the treatment of diabetic complications and other conditions associated with advanced glycosylation end products (J Carbohydrate Chem.. 12(6), 731-742, (1993). Diabetes, 41, January 1992, 26-29. European Patent Application, publication number 0339496 and United States Patent numbers 5128360 and 5238963) Indeed aminoguanidine is under evaluation in animal models for the treatment of diabetic complications (Diabetes 42, 221-232 1993 and Diabetologia, 35. 946-950).

To date there has been no indication that aminoguanidine or any other inhibitor of protein glycation would have a beneficial effect on Type II diabetes itself. As indicated above the emphasis has been focused upon the complications of diabetes. We have now discovered that aminoguanidine does show potential for use in the treatment and/or prophylaxis of Type II diabetes. In particular, aminoguanidine is indicated to delay or prevent the progression of non-insulin dependent diabetes from hypennsulinaemia to overt diabetes. This novel and surprising effect is considered to be due to the inhibition of protein glycation by aminoguanidine Accordingly, the present invention provides a method for the treatment and/or prophylaxis of Type II diabetes, which method comprises the administration, to a human or non-human mammal, of an effective non-toxic pharmaceutical^ acceptable amount of an inhibitor of protein glycation. such as aminoguanidine or a pharmaceutically acceptable derivative thereof Preferably, the invention provides a method for the prophylactic treatment of Type II diabetes, in particular delaying or preventing the progression from hypennsulinaemia to hyperglycaemia.

Suitable, inhibitors of protein glycation include protein and non-protein compounds, such as aminoguanidine and its derivatives or analogues, for example those disclosed in International Patent Application publication number WO 94/11490, European Patent Application, publication number 0339496 or hydrazines and hydrazides such as those disclosed in WO 94/11490 and United States Patent numbers 5218360 and 5238963, thiosemicarbazides such as those disclosed in Japanese Patent Application publication number 01056614; non-hydrazine glycation inhibitors such as the derivatives of pyridine N-oxide disclosed in JP08I75995; crosslink breakers such as phenacylthiazoiium bromide and its derivatives or analogues as disclosed in Nature. 1996;382.211-278; and the amino acid/protein derivatives disclosed in International Patent Application publication number 93/04690; the contents of the publications listed m this paragraph are incorporated herein by reference.

When used herein a 'protein giycation inhibitor' refers to an agent which inhibits the non-enzymatic glycation or glycosylation of proteins and glycoproteins (the Maillard reaction), or which prevent the formation of irreversible advanced glycation end-products, or which prevents the crosslinking of advanced glycation end-products or which cleave advanced glycation end-product cross links The protein glycation inhibition activity of a compound is assessed in conventional tests such as inhibition of the glycation of haemoglobin or other suitable protein (Analytical Biochemistry, 1988.175:347-360).

A suitable pharmaceutical^ acceptable derivative is a pharmaceutical^ acceptable salt, or a pharmaceutically acceptable solvate thereof Suitable pharmaceutically acceptable salts include acid addition salts.

Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate. ascorbate. methane-sulphonate, a-keto glutarate and a-glycerophosphate, especially the maleate salt Suitable pharmaceutically acceptable solvates include hydrates.

The protein glycation inhibitors of the invention may be prepared according to ^ conventional methods, such as the methods disclosed m the above mentioned publications including the publications incorporated herein by reference, for example aminoguanidine may be prepared according to the methods disclosed in J. Amer. Chem. Soc. 57,2730, (1935).

Salts and/or solvates may be prepared and isolated according to conventional procedures. 30 There is also provided the use of an inhibitor of protein glycation, such as aminoguanidine or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of Type II diabetes.

In a further aspect the present invention also provides protein glycation inhibitor such as aminoguanidine or a pharmaceutically acceptable derivative thereof, for use in the treatment of 35 and/or prophylaxis of Type II diabetes.

In the above mentioned treatment and/or prophylaxis the protein glycation inhibitor, such as, aminoguanidine or a pharmaceutically acceptable derivative thereof may be administered gsr se or preferably as a pharmaceutical composition also comprising a pharmaceutical!}' acceptable carrier.

Accordingly, the present invention also provides a pharmaceutical composition for the treatment and/or prophylaxis of Type II diabetes, which composition comprises a protein glycation inhibitor, such as aminoguanidine or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable earner therefor.

As used herein the term 'pharmaceutically acceptable' embraces compounds. compositions and ingredients for both human and veterinary use- for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.

The composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.

Usually the pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged.

Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders presented in sachets, may also be used.

In accordance with conventional pharmaceutical practice the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.

Typical earners include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate or sucrose.

Most suitably the composition will be formulated in unit dose form. Such unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0 1 to 500 mg, and more especially 0.1 to 250 mg.

Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.

In the above mentioned treatments the active compound , may be taken in doses such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg, generally about 0.5 to 10 mg That is in the range of from 1.429 x 10~3 to 85.714 mg/kg/day, more usually about 1.429 x 10"2 to 21.429 mg/kg/day, generally about 7.143 x 10'^ to 0.1429 mg/kg/day.

No unacceptable toxicological effects are obsen'ed when active compounds are administered in accordance with the above mentioned invention.

The following Example illustrates the invention but does not limit it in any way.

EXAMPLE Methodology of dbdb mouse model The obese db/db mouse is a genetic model of type 2 non-insulin dependent diabetes which is both insulin resistant and hyperglycaemic. Male animals were obtained at 6 weeks of age. Blood samples were taken by tail tip snip for measurement of pre-treatment blood glucose. Animals were allocated into treated and control groups such that the mean and standard deviation of the fasting blood glucose concentrations of each group was similar.

On day 0 of the study a group of obese animals and their lean litter mates were killed for measurement of baseline biochemistry and histology In addition one group of animals (control; | n = 14) were fed a standard diet and a further group received aminoguanidine (500mg/kg; n = 14) in the same diet Animals were allowed free access to food and water and their intake measured 15 daily. At weekly intervals 24hr urine output was also measured Mice (n = 7) were killed at 30 days and 85 days from commencement of treatment. Blood was taken for measurement of glucose and insulin concentrations and the pancreas removed for histological analysis and for measurement of pancreatic insulin.

Data from dbdb mouse model Food intake and body weight gain of the control and treated groups was similar throughout the experimental period Immediately prior to dosing obese animals were normoglycaemic (blood glucose 10 4 ± 25 0 97mM) but were hypennsulinaemic compared to their lean litter mates (serum lsulin 127 ± 37 ng/ml in obese animals 3.05 ± 1.03 ng/ml in leans). By day 30 of the dosing period the obese control group were hyperglycaemic (blood glucose 24.9 ± 1.0 mM) and had markedly lower serum insulin levels (30.75 ± 4.3 mM) compared to the pre-treatment values. By day 85 of the treatment period, fasting blood glucose had risen to 28.1 ± 2 mM and serum insulin 30 concentrations had fallen further, to 11.7 ± 1.8 ng/ml. Aminoguanidine attenuated the fall in fasting insulin concentrations (58.3 ± 13 ng/ml on day 30, 23.3 ± 4.1 ng/ml on day 85) and on day 85 had significantly reduced the prevailing fasting hyperglycaemia (21 ± 1.7 mM). Pancreatic insulin content of the aminoguanidine treated group of obese animals was twice that of the untreated animals (64.3 ± 17.8 ng/mg pancreas compared to 30.0 ± 2.6 ng/mg, 35 respective!}) From day 63 of the experimental period obese control animals were markedly polydypsic and polyuric compared to day 7. This increase in water intake and urine output is a characteristic of diabetes (hyperglycaemia) and was prevented by treatment with aminoguanidine (Figure 1). Similarly urinary glucose excretion increased steadily over the experimental period, in both untreated and treated animals, but from day 35 was lower in the 5 aminoguanidine treated group (Figure 1). The development of diabetes (hyperglycaemia) was associated with changes in islet morphology, and the islets of untreated control animals were markedly hypertrophic, disorganised and had irregular boundaries. On day 85 loss of 13-cells and inward collapse of the islet was evident. Islet insulin content was markedly depleted. On day 30 and 85 of the treatment period these changes in islet morphology were 10 partially ameliorated.

Claims (5)

WHAT WE CLAIM IS

1. The use of a protein glycation inhibitor, or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of Type II diabetes.

2. The use according to claim 1, for the prophylactic treatment of Type II diabetes.

3. The use according to claim 1 or claim 2, for delaying or preventing the progression from hypennsulinaemia to hyperglycemia.

4. The use according to any one of claims 1 to 3, wherein the protein glycation inhibitor is selected from aminoguanidine and its derivatives or analogues, hydrazine type compounds and hydrazide derivatives, thiosemicarbazides, derivatives of pyridine N-oxide and crosslink breakers such as phenacylthiazolium bromide and its derivatives or analogues.

5. The use according to any one of claims 1 to 4, wherein the protein glycation inhibitor is aminoguanidine,