C-proteinase inhibitors

Details C-proteinase inhibitors C-proteinase inhibitors

2000-02-04

2002-10-08

Fan, Jane (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S391000, C514S341000, C546S274400, C548S319500

Reexamination Certificate

active

06462063

ABSTRACT:

1. FIELD OF THE INVENTION
The present invention relates to a novel class of organic molecules capable of inhibiting the enzyme C-proteinase, pharmaceutical compositions comprising the C-proteinase inhibitory compounds and methods of using the compounds and compositions to regulate, modulate and/or inhibit collagen production and/or maturation as a therapeutic approach towards the treatment or prevention of myriad diseases related to, or associated with, unregulated collagen production.
2. BACKGROUND OF THE INVENTION
Collagen Structure
At present, nineteen different types of collagens have been identified. These collagens, which include fibrillar collagen types I, II and III, are synthesized as procollagen precursor molecules which contain peptide extensions at both their amino- and carboxy-termini. These peptide extensions, referred to as “pro-regions,” are designated as N- and C-propeptides, respectively.
The pro-regions are typically cleaved upon secretion of the procollagen triple helical precursor molecule from the cell to yield a mature triple helical collagen molecule. Upon cleavage, the “mature” collagen molecule is capable of association, for example, into highly structured collagen fibers. See e.g., Fessler and Fessler, 1978
, Annu. Rev. Biochem
. 47:129-162; Bornstein and Traub, 1979, in: The Proteins (eds. Neurath, H. and Hill, R. H.), Academic Press, New York, pp. 412-632; Kivirikko et al., 1984, in:
Extracellular Matrix Biochemistry
(eds. Piez, K. A. and Reddi, A. H.), Elsevier Science Publishing Co., Inc., New York, pp. 83-118; Prockop and Kivirikko, 1984
, N. Engl. J. Med
. 311:376-383; Kuhn, 1987, in:
Structure and Function of Collagen Types
(eds. Mayne, R. and Burgeson, R. E.), Academic Press, Inc., Orlando, Fla., pp. 1-42.
Diseases Associated With The Abnormal Production of Collagen
A variety of critical diseases have been linked to inappropriate or unregulated collagen production and/or maturation. These diseases include pathological fibrosis or scarring (including endocardial sclerosis), idiopathic interstitial fibrosis, interstitial pulmonary fibrosis, perimuscular fibrosis, Symmers' fibrosis, pericentral fibrosis, hepatitis, dermatofibroma, binary cirrhosis, alcoholic cirrhosis, acute pulmonary fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, kidney fibrosis/glomerulonephritis, kidney fibrosis/diabetic nephropathy, scleroderma/systemic, scleroderma/local, keloids, hypertrophic scars, severe joint adhesions/arthritis, myelofibrosis, corneal scarring, cystic fibrosis, muscular dystrophy (duchenne's), cardiac fibrosis, muscular fibrosis/retinal separation, esophageal stricture and payronles disease. Further fibrotic disorders may be induced or initiated by surgery, including scar revision/plastic surgeries, glaucoma, cataract fibrosis, corneal scarring, joint adhesions, graft vs. host disease, tendon surgery, nerve entrapment, dupuytren's contracture, OB/GYN adhesions/fibrosis, pelvic adhesions, peridural fibrosis, restenosis. One strategy for the treatment of these diseases is to inhibit the pathological overproduction of collagen. Thus, identification and isolation of molecules which control, inhibit and/or modulate the production of collagen are of major medical interest.
Relationship Between Collagen Formation and C-Proteinase
Recent evidence suggests that C-proteinase is the essential key enzyme that catalyzes the cleavage of the C-propeptide of, for example, fibrillar collagens, including type I, type II, and type III collagen. See e.g. Prockep et al., 1998
, Matrix Biol
. 16:399-408; Lee et al., 1997
, J. Biol. Chem
. 272:19059-19066; Suzuk et al., 1996
, Development
122:3587-3595.
C-proteinase was first observed in the culture media of human and mouse fibroblasts (Goldberg et al., 1975
, Cell
4:45-50; Kessler and Goldberg, 1978
, Anal. Biochem
. 86:463-469), and chick tendon fibroblasts (Duskin et al., 1978
, Arch. Biochem. Biophys
. 185:326-332; Leung et al., 1979
, J. Biol. Chem
. 254:224-232). An acidic proteinase which removes the C-terminal propeptides from type I procollagen has also been identified. Davidson et al., 1979
, Eur. J. Biochem
. 100:551.
A partially purified protein having C-proteinase activity was obtained from chick calvaria in 1982. Njieha et al., 1982
, Biochemistry
23:757-764. In 1985, chicken C-proteinase was isolated, purified and characterized from conditioned media of chick embryo tendons. Hojima et al., 1985
, J. Biol. Chem
. 260:15996-16003. Murine C-proteinase has been subsequently purified from media of cultured mouse fibroblasts. Kessler et al., 1986
, Collagen Relat. Res
. 6:249-266; Kessler and Adar, 1989
, Eur. J. Biochem
. 186:115-121. Finally, the cDNA encoding human C-proteinase has been identified (see, e.g., Takahara et al., 1994
, J. Biol. Chem
. 269:26280-26285; Li et al., 1996
, Proc. Natl. Acad. Sci. USA
93:5127-5130; Kessler et al., 1996
, Science
271:360-362.
C-Proteinase Inhibitors
Experiments conducted with purified forms of chick and mouse C-proteinases indicate that C-proteinase is instrumental in the formation of functional collagen fibers. Fertala et al., 1994
, J. Biol. Chem
. 269:11584. As a consequence of its critical role in collagen production and maturation, scientists have sought to identify compounds that inhibit C-proteinase. See e.g., Hojima et al., supra. Compounds identified to date include metal chelators (e.g., EDTA, phenanthroline, EGTA, basic amino acids (e.g., lysine and arginine), peptides (e.g., chymostatin, pepstatin A, and concanavalin A), proteins (e.g., &agr;
2
-macroglobulin, ovostatin, and fetal bovine serum), metals ions (e.g., Zn
2+
, Cu
2+
, and Cd
2+
), reducing agents (e.g., dithiothreitol), detergents (e.g., sodium dodecyl sulfate (SDS)) and certain salts and buffers (e.g., phosphate, ammonium sulfate, sodium chloride and tris hydrochloride). In contrast, microbial inhibitors such as leupeptin, phosphoramidon, antipain, bestatin, elastinal, and amastatin are considered to have weak or no effect on the activity of C-proteinase. For references discussing the various C-proteinase inhibitors identified to date, see Leung et al., supra; Ryhänen et al., 1982
, Arch. Biochem. Biophys
. 215:230-236; W097/05865; and the references cited therein.
Matrix Metalloproteinase Hydroxamic Acid Inhibitors
C-proteinase belongs to the matrix metalloproteinase (MMP) superfamily of zinc endopeptidases which are involved in tissue remodeling. Members of the MMP family include MMP-1 (human collagenase), MMP-2 (gelatinase), and MMP-9 (human gelatinase B). See e.g. W098/34918; Krumme et al., 1998
, FEBS Lett
. 436:209-212. The MMPs are characterized by an active site zinc ion that plays an essential role in the enzymatic activity of MMPs. Rational drug discovery efforts, involving the inhibition of MMPs, have focused on inhibitor classes that contain a functional group that can coordinate the zinc ion and thereby inactivate the target MMP. See e.g. Krumme et al., supra. One such inhibitor class are hydroxamic acids. As revealed by the x-ray crystal structure determination of hydroxamic acid:MMP cocrystals, the hydroxamic acid coordinates the active site zinc in a bidentate manner via the hydroxyl and carbonyl oxygens of the hydroxamic group. See Grams et al., 1995
, Biochem
. 34:14012-14020; Bode et al., 1994
, EMBO J
., 13:1263-1269. Despite their potent affinity as zinc coordinators, hydroxamic acids demonstrate a considerable degree of specificity within the MMP family. Thus a potent inhibitor of MMP-1 (human collagenase) may have only minimal potency against another MMP such as C-proteinase. Thus the development of potent hydroxamic acid inhibitors against a particular MMP requires considerable research effort and experimentation.
Development Of Compounds To Inhibit C-Proteinase Activity
In view of its essential role in the formation and maturation of collagen, C-proteinase provides an ideal therapeutic target towards the treatment or prevention of disorders related to, or associated with, unregulated collagen production

Affiliated with

Also associated with

Rating

C-proteinase 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 C-proteinase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and C-proteinase inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2937040