Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-08-02
2001-11-20
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C424S130100, C514S019300
Reexamination Certificate
active
06319893
ABSTRACT:
The invention relates to a method in which, by reducing dipeptidyl peptidase IV (DP IV) or DP IV-analogous enzyme activity in the blood of a mammal by administration of activity-reducing effectors, the endogenous (or additionally exogenously administered) glycogenolytically active peptide glucagon or analogues thereof is/are degraded to a reduced extent by DP IV and DP IV-like enzymes, thereby reducing or delaying the decrease in concentration of that peptide hormone or analogues thereof.
Owing to that increased stability of (endogenous or exogenously administered) glucagon and its analogues brought about by the action of DP IV effectors, thereby making them available in greater number for the glycogenolytic stimulation of the glucagon receptors of, in particular, liver cells, the duration of activity of the body's own glucagon changes, consequently resulting in stimulation of the catabolic carbohydrate metabolism of the organism treated.
As a result, the blood sugar level in the serum of the treated organism rises above the glucose concentration characteristic of hypoglycaemia. Thereby, metabolic anomalies, such as hypoglycaemic states resulting from reduced glucose concentrations in the blood, can be prevented or alleviated.
In addition to proteases involved in non-specific proteolysis, which ultimately causes the degradation of proteins into amino acids, regulatory proteases are known which take part in the functionalisation (activation, deactivation, modulation) of endogenous peptide active substances (Kirschke et al., 1995; Kräusslich & Wimmer, 1987). Especially in connection with immune research and neuropeptide research, a number of such so-called convertases, signal peptidases or enkephalinases have been discovered (Gomez et al., 1988; Ansorge et al., 1991).
In view of the frequency with which the amino acid proline occurs in a large number of peptide hormones and the associated structural characteristics of those peptides, a function analogous to that of the signal peptidases is being discussed for proline-specific peptidases (Yaron & Naider, 1993; Walter et al., 1980; Vanhoof et al., 1995). By its special structure, proline in those peptides determines both conformation and stability of those peptides by protecting them from being degraded by non-specific proteases (Kessler, 1982).
Enzymes that have a highly specific structure-altering effect on proline-containing sequences (HIV protease, cyclophilin etc.) are attractive targets for current active substance research. In particular for the peptidases prolyl endopeptidase (PEP) and dipeptidyl peptidase IV (DP IV) which cleave after the proline, relationships between modulation of the biological activity of natural peptide substrates and their selective cleavage by those enzymes could be made plausible. Thus, it is assumed that PEP plays a role in learning and in the memory process and that DP IV is involved in signal transmission during the immune response (Ishiura et al., 1990; Hegen et al., 1990).
As with the extraordinary proline specificity of those enzymes, there is discussion about their high selectivity for the amino acid alanine inside typical recognition regions in substrates of those enzymes, according to which alanine-containing peptides can adopt similar conformations to the structurally analogous proline-containing peptides. Such properties of alanine-containing peptide chains have recently been demonstrated by point mutation (exchange of proline for alanine) (Dodge & Scheraga, 1996).
DP IV and DP IV-analogous activity (for example cytosolic DP II has a substrate specificity virtually identical to that of DP IV) occurs in the blood circulation where it removes dipeptides from the N-terminus of biologically active peptides in a highly specific manner when proline or alanine form the adjacent residues of the N-terminal amino acid in their sequence. On the basis of that cleavage site specificity, it is assumed that that enzyme and analogues are involved in the regulation of polypeptides in vivo (Vanhoof et al., 1995).
Blood sugar concentrations that are too low may lead to pathological states in the human or animal organism. In particular, after accidents, so-called hypoglycaemic shock may occur which may lead in patients to hyperorexia, sweating and even to loss of consciousness and death.
It was therefore a problem of the present invention to provide agents for preventing or alleviating pathological metabolic anomalies of mammalian organisms, such as acute or chronic hypoglycaemia.
In particular, it was a problem of the present invention to provide agents by means of which carbohydrate reserves, for example of the liver, can be rapidly mobilised.
Those problems are solved according to the invention by the use of activity-reducing effectors of dipeptidyl peptidase IV (DP IV) and DP IV-analogous enzyme activity to raise the blood sugar level in a mammalian organism.
It is already known to use activity-reducing effectors of DP IV to lower the blood sugar level of mammalian organisms. In so doing, the degradation of incretins, which stimulate glucose disposal, by DP IV is stopped.
It is therefore especially surprising that activity-reducing effectors of DP IV and DP IV-analogous enzyme activity can be used to raise the blood sugar level. Presumably, that effect relies on the following mechanisms:
In glucose metabolism and catabolism in the human and animal body, a distinction can be made in principle between two phases:
1. In the first phase, following food intake, increased release of incretins takes place (i.e. hormones that stimulate insulin secretion of the pancreas, such as gastric inhibitory polypeptide 1-42 (GIP
1-42
) and glucagon-like peptide amide-1 7-36 (GLP-1
7-36
)), resulting in increased insulin production and, as a consequence, in increased degradation of the glucose supplied by food intake.
Incretins are, however, substrates of DP IV, since the latter is able to remove the dipeptides tyrosinyl alanine and histidyl alanine from the N-terminal sequences of incretins in vitro and in situ (Mentlein et al., 1993). Consequently, if DP IV is present, degradation of the incretins occurs, which in turn leads to reduced glucose disposal.
By inhibiting the DP IV and DP IV-analogous enzyme activity in vivo, therefore, it is possible effectively to suppress excessive degradation of the incretins and consequently to increase glucose disposal:
DP IV inhibition leads to stabilisation of the incretins,
the extended life of the incretins in the blood circulation intensifies their insulinotropic and insulin-sensitising action,
the consequently increased and more effective insulin release brings with it an increased glucose tolerance (Demuth et al., 1996).
It has been demonstrated in diabetic rats that the corresponding DP IV inhibitors can be used effectively to modulate the control system described (Pederson et al., 1998). That phase lasts approximately 120 minutes from the time of food intake.
After that so-called postprandial phase has elapsed, the secretion of incretins is stopped and any already existing incretins are degraded by DP IV. As a result, insulin production falls, bringing glucose disposal to an end.
2. In order to maintain the physiologically necessary glucose concentration of approximately 5.5 mmol/l between food intakes, in the second phase stored glycogen is degraded, for which glucagon is released from the pancreatic A-cells. Glucagon has, therefore, an opposite effect to insulin and hence also to the incretins.
In the case of three meals a day, the human body is accordingly under GLP-1/GIP and insulin control for approximately 6 hours (3×120 minutes), but under glucagon control for 18 hours.
It has been established that DP IV is endogenously released from the same secretory granules of the A-cells as glucagon and that that release may take place simultaneously with the release of glucagon and the onset of glucagon action. According to the invention, it has now been found that glucagon both in vitro and in vivo is degraded and thereby deactivated by DP IV and DP IV-analogous enzym
Demuth Hans-Ulrich
Hoffmann Torsten
Kuhn-Wache Kerstin
Rosche Fred
Brown Rudnick Freed & Gesmer
Hofer Mark A.
Meller Mike
Naff David M.
Probiodrug
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