Oligopeptide aldehydes useful as specific inhibitors of enteroki

Details Oligopeptide aldehydes useful as specific inhibitors of enteroki Oligopeptide aldehydes useful as specific inhibitors of enteroki

1985-01-07

1986-06-03

Phillips, Delbert R.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 17, 514 18, 530331, 530330, 530329, C07K 702, C07K 706, C07K 508, A61K 3743

Patent

active

045930180

DESCRIPTION:

BRIEF SUMMARY
This invention relates to peptides and is particularly concerned with new oligopeptides having selective inhibitory activity against enterokinase.
Acute necrotising pancreatitis results from runaway activation of digestive enzyme precursors within the pancreas itself. We have shown that the disease is initiated by the displacement of enterokinase from the proximal intestine into the circulation, its carbohydrate dependent uptake by the liver, transfer in catalytically active form to bile the entry of bile-bourne active enterokinase into the pancreatic ducts.
We have now prepared oligopeptide aldehydes which exhibit selective inhibitory activity against the proteinase enterokinase (EC 3.4.21.9) but not against other proteinases of the type inhibited by leupeptin and antipain.
Accordingly the present invention provides a compound of the general formula: ##STR2## wherein n is an integer from 2 to 6, m is an integer from 2 to 4, p is an integer from 1 to 3, R is H, an amino protecting group conventionally used in peptide chemistry or a solid phase support, R.sub.1 is H or a carboxy protecting group conventionally used in peptide chemistry and R.sub.2 is H or alkyl or ##STR3##
In the compound of formula I, it is preferred that m be 3 and R.sub.2 be ##STR4## so that the terminal amino aldehyde residue of the oligopeptide is argininal. Further compounds of interest are those in which m is 4 and R.sub.2 is H or a C.sub.1 -C.sub.4 alkyl group e.g. methyl, so that the terminal amino aldehyde residue is lysinal or an N-alkyl lysinal. Higher or lower homologues of argininal or lysinal are also of interest in which the trimethylene or tetramethylene group is replaced by monomethylene or dimethylene.
It is also preferred that p represent 1 so that there is at least one aspartic acid residue present in the block of amino acids linked to the amino aldehyde. There will be at least two amino acid units directly bonded to the terminal amino aldehyde unit. These amino acid units will normally be the same amino acid unit but need not necessarily be the same. For example, although aspartic acid units are preferred, one or more may be replaced for example glutamic acid.
n will be an integer of at least 2 up to 6 and it is preferred that n be 2 or 4 since we have found that the selective inhibitory action of these oligopeptides is at its greatest for the tripeptide and pentapeptide.
It is also preferred that the C-terminal amino aldehyde have L configuration at the .alpha.-carbon atom but L configuration is not essential at the other .alpha.-carbon atoms in the oligopeptide. D configuration may confer resistance to degradation in vivo.
It is also preferred that the terminal amino aldehyde be L-argininal and that the amino dicarboxylic acids linked to it all be aspartic acid so that the oligopeptide is a polyaspartyl argininal.
The compounds of major interest are the compounds in which the .gamma.-carboxy group in the amino dicarboxylic acid units is unprotected, that is to say R.sub.1 is H, as the carboxy protecting groups must be removed to maximise the inhibitory activity. The inhibitory activity is influenced by the presence or absence of the amino protecting group R so that R can be H, a protecting group in the active compounds or a solid phase support. The invention extends to the protected as well as the unprotected forms of the oligopeptides as, as a result of the synthetic methods employed, the oligopeptides are normally first obtained in protected form and the protecting groups are removed in a final stage of synthesis in accordance with conventional methods used in peptide chemistry.
When the terminal amino group is to be protected, it is protected with any of the protecting groups conventionally used, for example tertiary butyloxy carbonyl, benzyloxy carbonyl or acetyl. These groups are of interest primarily because of their stability during the reaction conditions conventionally encountered in peptide synthesis and their ease of removal under acid conditions. However, other amino protecting groups can be used, for exa

REFERENCES:
The Journal of Antibiotics, Jun. (1971), pp. 402-404, vol. 24.
Jones et al, Gut 23, No. 11, 939-943 (1982), "Antiproteinase Chemotherapy of Acute Experimental Pancreatitis Using the Low Molecular Weight Oligopeptide Aldehyde Leupeptin".
Hermon-Taylor et al, Clinica Chimica Acta, 109 (1981), 203-209, "Cleavage of Peptide Hormones by .sub.2 -Macroglobulin-Trypsin Complex and Its Relation to the Pathogenesis and Chemotherapy of Acute Pancreatitis".
Abstract of Cliffe et al, "The Selective Inhibition of Enterokinase by Synthetic Peptide Aldehydes Based on the Activation Peptide of Trypsinogen".

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