Peptidyl derivatives as metalloproteinase inhibitors

Details Peptidyl derivatives as metalloproteinase inhibitors Peptidyl derivatives as metalloproteinase inhibitors

1995-02-06

1998-02-03

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514277, 514365, 514374, 514385, 514403, 514428, 514438, 514461, 514575, 544242, 546348, 548205, 548215, 5483351, 5483731, 548517, 548566, 549 59, 549 76, 549496, 562623, C07K25904, A61K 3119, A61K 31505

Patent

active

057144915

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB94/00895 filed Aug. 27, 1994.


FIELD OF THE INVENTION

This invention relates to a novel class of peptidyl derivatives, to processes for their preparation and to their use in medicine.


BACKGROUND TO THE INVENTION

In normal tissues, cellular connective tissue synthesis is offset by extracellular matrix degradation, the two opposing effects existing in dynamic equilibrium. Degradation of the matrix is brought about by the action of proteinases released from resident connective tissue cells and invading inflammatory cells, and is due, in part, to the activity of at least three groups of metalloproteinases. These are the collagenases, the gelatinases (or type-IV collagenases) and the stromelysins. Normally these catabolic enzymes are tightly regulated at the level of their synthesis and secretion and also at the level of their extracellular activity, the latter through the action of specific inhibitors, such as .alpha..sub.2 -macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form inactive complexes with metalloproteinases.
The accelerated, uncontrolled breakdown of connective tissues by metalloproteinase catalysed resorption of the extracellular matrix is a feature of many pathological conditions, such as rheumatoid arthritis, corneal, epidermal or gastric ulceration; tumour metastasis or invasion; periodontal disease and bone disease. It can be expected that the pathogenesis of such diseases is likely to be modified in a beneficial manner by the administration of metalloproteinase inhibitors and numerous Wahl, R.C. et al Ann. Rep. Med. Chem. 25, 175-184, Academic Press Inc., San Diego (1990)!.
Although numerous metalloproteinase inhibitors have been described, many have not been suitable for further development as medicines since they have lacked any useful activity when administered orally at pharmaceutically acceptable doses. What is therefore needed is a potent and selective orally active compound with a good duration of action.


SUMMARY OF THE INVENTION

We have now found a new class of peptidyl derivatives, members of which are metalloproteinase inhibitors and which, in particular, advantageously possess a potent and selective inhibitory action against gelatinase. In addition, compounds according to the invention have surprisingly good oral bioavailability, and after oral administration have an advantageously longer duration of action than related known compounds, such as those described in International Patent Specification No. WO92/09564.
Thus according to one aspect of the invention we provide a compound of formula (1) ##STR1## an acyl group!, carboxyl (--CO.sub.2 H), esterified carboxyl, --SR.sup.6 or --P(O)(X.sub.1 R.sup.7)--X.sup.2 R.sup.8 group, where X.sup.1 and X.sup.2, which may be the same or different, is each an oxygen or sulphur atom and R.sup.7 and R.sup.8, which may be the same or different each represents a hydrogen atom or an optionally substituted alkyl, aryl, or aralkyl group; alkenyl, aryl, aralkyl, heteroaralkyl or heteroarylthioalkyl group; Ar is an aryl or heteroaryl group, Z.sup.1 and Z.sup.2, which may be the same or different, is each a bond or a heteroatom, and m is zero or an integer 1 to 6 with the proviso that when m is zero, Z.sup.2 is a bond, and Z.sup.1 is a heteroatom; R.sup.9 and R.sup.10 which may be the same or different is each an optionally substituted alkyl or alkenyl group optionally interrupted by one or more --O-- or --S-- atoms or --N(R.sup.12)-- groups (where R.sup.12 is a hydrogen atom or an optionally substituted alkyl group), or an optionally substituted cycloalkyl, cycloalkenyl, aryl or heteroaryl group, or R.sup.9 and R.sup.10 together with the carbon atom to which they are attached are linked together to form an optionally substituted cycloalkyl an integer 1 or 2! or --N(R.sup.12)--, and R.sup.11 is a hydrogen atom or an aliphatic, cycloaliphatic, heterocyclo-aliphatic, aromatic, or heteroaromatic group; hydroxyl group, or is linked to the atom or group Het in R.sup.5 to form a chain --X-Alk--

REFERENCES:
Wahl et al., Biochemistry and Inhibition of Collagenase and Stromelysin, Ann. Rep. Med. Chem., 1990, vol. 25, pp. 177-184.
Porter et al., "Organometallic Reagents In Organic Synthesis", Smithkline Beecham Research Symposium, Mar. 25-25, 1993.
Stack et al., "Comparison of Vertebrate Collagenase And Gelatinase Using a New Fluorogenic Substrate Peptide", The Journal of Biological Chemistry, vol. 264, No. 8, pp. 4277-4281, (1989).
Moses et al., "Inhibitors of Angiogenesis", Bio/Technology, vol. 9:630-634, (1991).
Folkman et al., "Angiogenic Factors", Science, vol. 235:442-447, (1987).
WessJohann et al., "A New Versatile Synthesis of Ring-Substituted 2-Cyclopropylglycines and Related Amino Acids", Chem. Ber., vol. 125:867-882, (1992).

Affiliated with

Also associated with

Rating

Peptidyl derivatives as metalloproteinase 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 Peptidyl derivatives as metalloproteinase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Peptidyl derivatives as metalloproteinase inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-662564