Matrix metalloproteinase inhibitors and down-regulators

Details Matrix metalloproteinase inhibitors and down-regulators Matrix metalloproteinase inhibitors and down-regulators

2000-11-20

2003-09-23

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S011400, C514S015800, C530S317000, C530S328000, C530S334000, C530S344000, C530S354000, C530S360000, C435S219000

Reexamination Certificate

active

06624144

ABSTRACT:

This application is the national phase under 35 U.S.C. §371 of PCT International Application No. PCT/FI99/00204 which has an International filing date of Mar. 17, 1999, which designated the United States of America.
A The present invention relates to novel matrix metalloproteinase (MMP) inhibitors and down-regulators, to a process for the preparation of these inhibitors, to pharmaceutical compositions comprising these inhibitors/downregulators, to the use of the novel matrix metalloproteinase inhibitors for the manufacture of pharmaceutical and research preparations, to a method for inhibiting and down-regulating MMP-dependent conditions either in vivo or in vitro, to a method for inhibiting formation, synthesis, expression and/or functions as well as actions of matrix metalloproteinases, and to the use of the novel MMP inhibitors in biochemical isolation and purification procedures of matrix metalloproteinases.
Matrix metalloproteinases (MMPs) constitute a superfamily of genetically closely related proteolytic enzymes capable of degrading almost all the constituents of extracellular matrix and basement membrane that restrict cell movement. MMPs also process serpins, cytokines and growth factors as well as certain cell surface components (Woessner, 1991; Birkendal-Hansen, 1995; Chandler et al., 1997). MMPs are thought to have a key role in mediating tissue remodeling and cell migration during morphogenesis and physiological situations such as wound healing, trophoblast implantation and endometrial menstrual breakdown. MMPs are further involved in processing and modification of molecular phenomena such as tissue remodeling, angiogenesis, cytokine, growth factor, inte grin and their receptor processing (Chandler et al., 1997). MMPs also mediate release and membrane-bound proteolytic processing of tumor necrosis factor (TNF-&agr;) by bacterial-virulence factor induced monocytes. This event is mediated by a membrane-bound metalloproteinase TACE (TNF-&agr; activating enzyme). Thus MMP-inhibitors, such as the novel peptides presented in this invention, can i.a. prevent activation of TNF-&agr; by blocking this type of activating enzymes (Shapira et al., 1997).
Several studies have shown that the expression and activities of MMPs are pathologically elevated over the body's endogenous anti-proteinase shield in a variety of diseases such as cancer, metastatis, rheumatoid arthritis, multiple sclerosis, periodontitis, osteoporosis, osteosarcoma, osteomyelitis, bronchiectasis, chronic pulmonary obstructive disease, and skin and eye diseases. Proteolytic enzymes, especially MMPs, are believed to contribute to the tissue destruction damage associated with these diseases.
There is a variety of other disorders in which extracellular protein degradation/destruction plays a prominent role. Examples of such diseases include arthritides, acquired immune deficiency syndrome (AIDS), burns, wounds such as bed sores and varicose ulcers, fractures, trauma, gastric ulceration, skin diseases such as acne and psoriasis, lichenoid lesions, epidermolysis bollosa, aftae (reactive oral ulcer), dental diseases such as periodontal diseases, peri-implantitis, jaw and other cysts and root canal treatment or endodontic treatment, related diseases, external and intrinsic root resorption, caries etc.
At least 20 members of the MMP-superfamily are known (Birkendal-Hansen, 1995; Pei & Weiss, 1996; Llano et al., 1997), and the number of MMP-family members and their cellular origins is growing all the time. Each of the MMP enzymes contains a putative tridentate Zn
2+
binding site which is believed to constitute the active site in the enzyme. Very recently, three new members of the MMP-family were discovered by screening cDNA libraries for homologies to conserved regions of the known MMP genes and named the membrane-type matrix metalloproteinases-1, -2, and -3 (MT-MMP-1, -2, and-3). Based on their predicted amino acid sequences, each of the MT-MMPs like almost all previously characterized MMPs, contains (i) a candidate leader sequence, (ii) a propeptide region which includes a highly conserved PRCGXPD(SEQ ID NO:12) sequence that helps to stabilize the MMP zymogen in a catalytically inactive state, (iii) a zinc-binding catalytic domain, and (iv) a hemopexin-like domain near their respective C-termini. In addition, in a pattern similar to that described for stromelysin-3, each of the MT-MMPs contains a short amino acid insert sandwiched between their pro- and catalytic domains that encodes a potential recognition motif for members of the proprotein convertase family. Despite their considerable similarity to other MMP family members, however, only the MT-MMPs contain approximately 75-100 amino acid extensions at their C-termini, each of which includes a hydrophobic stretch consistent with the presence of a transmembrane (TM) domain. Thus, in contradistinction to all other MMPs, the MT-MMPs are expressed as membrane-associated ectoenzymes rather than soluble proteins (Pei & Weiss, 1996).
A comprehensive review of the MMP-family members, their activation, modes of action, their inhibition by various natural proteins (endogenous inhibitors) and synthetic compounds as well as details of the involvement of MMP family members in various pathological conditions and diseases is given by Woessner (1991); Krane (1994); Birkendal-Hansen et al. (1993); and Birkendal-Hansen (1995), the whole disclosures of which are incorporated herein by reference. In the scope of the present invention the term matrix metalloproteinase (MMP) refers to all discovered MMPs.
The gelatinase A or 72 kDa MMP-2 and gelatinase B or 92 kDa MMP-9 were originally described as type IV collagenases because they appeared to be essential enzymes for the degradation of the basement membrane (Tryggvason et al., 1987). Cells need to traverse the endothelial basement membrane during entry to and exit from the circulation. This is also a critical key step in the metastatic cascade tumor cells have to accomplish before they can metastasize to distant organs. MMP-2 and MMP-9 may also have a function in other steps of the metastatic cascade such as in angiogenesis (Hanahan & Folkman, 1996; Volpert et al., 1996) and local tumor invasion (Stetler-Stevenson et al., 1993).
Because MMPs are potential targets for therapeutic intervention, much work has been focused on the design of synthetic metalloproteinase inhibitors. Many MMP-inhibiting compounds containing reactive zinc-chelating groups such as thiol, hydroxamate, EDTA, phosphonamidate, phosphinate etc. have been developed (Beckett et al., 1996). Some of the peptidomimetics have shown beneficial effects in animal models of metastasis, arthritis, and other inflammatory diseases. Tumor cell invasion can also be inhibited by the native MMP inhibitors TIMP-1 (tissue inhibitor of metalloproteinase) and TIMP-2. MMPs can also be inhibited by peptides based on the highly conserved prodomain region of MMPs that is important for latency of MMPs (Park et al., 1991; Melchiori et al., 1992; Fotouhi et al., 1994). In addition, tetracyclines and their nonantimicrobial chemically-modified (CMT) as well as anthracycline derivatives have been found to inhibit MMPs (Golub et al., 1992; Sorsa et al., 1994).
Although the above discussion shows that some inhibitors for MMPs do exist and have been investigated, the tests are still mostly at the experimentation stage and no clinically acceptable inhibitor for MMPs exists as a therapeutic or prophylactic drug for any of the pathological states and diseases potentially connected with MMPs. Adverse side effects which have been detected in the above described MMP inhibitors include, for instance, toxicities (synthetic peptides), antimicrobial activities (tetracyclines), etc.
An alternative to rational molecular design is to screen libraries of random peptides or other chemicals to find lead compounds binding to target molecules. In particular, peptide libraries displayed on the surface of bacteriophage have often yielded valuable binding peptides to target proteins. However, it has been more

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