Serine protease inhibitors

Details Serine protease inhibitors Serine protease inhibitors

1998-03-30

2000-10-03

Davenport, Avis M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 19, 514 20, 530300, 530331, 530332, A61K 3800, A61K 3802, C07K 500, C07K 700

Patent

active

061273406

DESCRIPTION:

BRIEF SUMMARY
This invention relates to enzyme inhibitors and enzyme substrates, particularly those of trypsin-like or chymotrypsin-like enzymes, and to their use for example in the treatment or prevention of thrombosis.
Cardiovascular disease is a major cause of mortality, with incidence across the world higher than that of cancer. Acute events in the disease state, such as myocardial infarction, stroke, peripheral arterial occlusion and venous thromboembolic disease have recently been understood to be precipitated by formation of thromboembolic clots. This clot formation, as well as the aetiology of the disease state, e.g. formation of atheromatous plaque, has been shown to be mediated by the coagulation serine protease enzymes which control also the normal haemostatic balance of the blood. Modulation of any one coagulation protease, especially Factor VIIa. Factor Xa or thrombin, has been shown to control thrombogenesis. This has led to the development of inhibitors of serine protease enzymes to prevent thrombotic events in the clinic.
The family of serine protease enzymes all cleave peptide bonds by a mechanism involving the catalytic triad of Asp-His-Ser residues in the active site of the enzymes. Serine protease inhibitors have been designed which use functional groups, e.g. CO--H, B(OH).sub.2, P(O)(OR).sub.2, beta lactam, chloromethylketone, to interact with the triad and thereby block activation of the substrates.
However, serine proteases (Protein C. Plasmin) are also involved in thrombolysis and other physiological pathways, and broad inhibition of the coagulation serine proteases has been shown to be difficult to control. Thus, it can be desirable to make inhibitors selective for one target protease. Such selective inhibitors have been prepared by making peptide inhibitors comprising peptide sequences that bind preferentially to subsites unique in the target protease. Typically these sequences mimic the structure around the scissile bond of the natural substrate of the protease, which is fibrinogen in the case of thrombin. For example, selective peptide inhibitors of thrombin typically incorporate a sequence based on Phe-Pro, or more generally (aa)-Pro, where (aa) is some hydrophobic amino acid or analogue thereof
The amino acid residue which provides the carbonyl group of the scissile bond of a peptide sequence is designated "P1". Successive amino acid residues on the N-terminal side of residue
P1 are designated P2, P3, P4, . . . etc; amino acid residues on the C-terminal side of residue P1 are designated P1', P2', P3'. . . . In fibrinogen, P1' is glycine and P2' is proline. The protease contains a "specificity pocket" which recognises the side chain of the P1 amino acid. Thrombin belongs to a family of serine protease inhibitors described as "trypsin-like": the trypsin-like proteases normally recognise P1 residues with arginine-like or serine-like side chains. There is also a chymotrypsin-like family of serine protease inhibitors whose specificity pocket recognises phenylalanine-like and alanine-like side chains on the P1 residue.
Peptide inhibitors of serine proteases have been made in which the P1 terminal carboxy group is replaced by another acid group, e.t. a boronic acid group or a phosphorus oxyacid function. The P1 terminal carboxy or heteroatom analogue group may be derivatised, for example to form an ester, an alcohol, a thiol or an amine or to replace the OH groups of boronic acid with fluorine. The identity of the derivative moiety is not critical and may be selected according to the desired use of the target compound. Peptide inhibitors having a boron or phosphorus heteroatom analogue group at the P1 residue are described in, for example, WO 92/07869 and EP 0471651. Included herein by reference is U.S. Pat. No. 5,288,707, which is equivalent to EP 0471651 as well as U.S. Ser. No. 08/317,837 derived from WO 92/07869. Inhibitors having a P1 sulphonic acid group and derivatives thereof are described in Wong, S. C., Green, G. D. J., and Shaw, E., J.Med.Chem., 1978, 21, 456-459. Inactivation of trypsi

Affiliated with

Also associated with

Rating

Serine protease inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Serine protease inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Serine protease inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-195540