Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-09-27
2002-07-09
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S330000, C514S210030, C514S562000, C514S329000, C514S459000, C514S248000, C514S408000, C514S231200, C514S415000
Reexamination Certificate
active
06417229
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to new methods of using certain &agr;-sulfonylamino hydroxamic acid inhibitors of matrix metalloproteinases in the treatment of diseases, conditions and disorders of the peripheral or central nervous system, including but not limited to Alzheimer's disease, stroke/cerebral ischemia, head trauma, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, migraine, cerebral amyloid angiopathy, AIDS, age-related cognitive decline; mild cognitive impairment and prion diseases, and pharmaceutical compositions useful therefor.
The compounds of the present invention are inhibitors of zinc metalloendopeptidases, especially those belonging to the matrix metalloproteinase (also called MMP or matrixin) and reprolysin (also known as adamylsin) subfamilies of the metzincins (Rawlings, et al.,
Methods in Enzymology
, 248, 183-228 (1995) and Stocker, et al.,
Protein Science
, 4, 823-840 (1995)).
The MMP subfamily of enzymes, currently contains seventeen members (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16, MMP-17, MMP-18, MMP-19, MMP-20). The MMP's are most well known for their role in regulating the turn-over of extracellular matrix (ECM) proteins and as such play important roles in normal physiological processes such as reproduction, development and differentiation.
In the central nervous system, the ECM not only serves structural and adhesive functions but also stimulates intracellular signaling pathways in response to association of the matrix with cell surface proteins. (Yong et al.,
Trends in Neuroscience
, 21, 75-80 (1998)) Excessive expression of MMP's is believed to contribute to the pathogenesis of tissue destructive diseases such as arthritis, multiple sclerosis (MS) and cancer, conditions where inflammation and invasive processes play important roles. In Alzheimer's Disease (AD) and age-matched control samples, the expression of MMP's, particularly MMP-9 and MMP-2, is increased. The link between MMP's, AD and the ECM is supported by in vitro and in vivo evidence. In clinical samples taken from stroke, MS, amyotrophic lateral sclerosis (ALS) patients, increased expression of MMP's has also been documented. In AD, astrocytes produce inflammatory mediators and ECM proteins which surround neuritic plaques.
Like other members of the matrix metalloproteinase family, MMP-2 (72 kDa type IV collagenase or Gelatinase A) and MMP-9 (92 kDa type IV collagenase or Gelatinase B) are calcium-requiring, zinc containing endopeptidases which are secreted from cells in a latent pro-enzyme form (Yong et al., supra). These MMP's attack type IV collagen, laminen and fibronectin, the major components of the ECM surrounding cerebral blood vessels. Because of the dire consequences of inappropriate or unbalanced activity, they are tightly regulated by three independent mechanisms: proenzyme activation, gene transcription and inhibition by their endogenous inhibitor TIMP-1 (Borden and Heller,
Critical Reviews in Eurkaryotic Gene Expression
, 7, 159-178, (1997)). The expression of MMP-9 is induced by growth factors and inflammatory cytokines in an NF-&kgr;B and AP-1 dependent manner (Bond et al.,
FEBS Letters
, 435, 29-34, (1998)). MMP-2 is generally constitutively expressed; however, its mRNA can be modulated by some of the same factors which modulate MMP-9 expression (Gottschall and Deb,
Neuroimmunomodulation
, 3, 69-75, (1996)).
Additionally, in AD hippocampus, MMP-9 protein is increased as much as four-fold (Backstrom et al.,
J. Neurochemistry
, 58, 983-92 (1992)). The enzyme is predominantly found in its latent or proenzyme form in close proximity to extracellular amyloid plaques (Backstrom et al.,
J. Neuroscience
, 16, 7910-19 (1996)). Similar observations were made in aged beagles. In amyloid-positive samples, statistically significant increases in latent MMP-9 were seen as compared with amyloid-negative samples (Lim et al.,
J. Neurochemistry
, 68, 1606-11 (1997)).
The link between MMPs, AD and the ECM is supported by additional evidence (Perlmutter et al.,
J. Neuroscience Res
., 30, 673-81 (1991); Brandan and Inestrosa,
Gen. Pharmacology
, 24, 1063-8 (1993); Eikelenboom et al.,
Virchows Archiv
, 424, 421-7 (1994); Luckenbill-Edds,
Brain Res. Revs
., 23, 1-27 (1997)). Laminin is induced by brain injury and co-localizes with amyloid deposits in AD. In AD tissue, native human laminin was localized in large punctate, extracellular deposits which co-localize with plaques. Antibodies to the neurite-outgrowth promoting domains of laminin B2 or A chains localize to glia or capillary basement membranes, respectively. In control brains, laminin immunoreactivity is only found in capillaries (Murtomaki et al.,
J. Neuroscience Res
., 32, 261-73 (1993)). In a murine model of neurodegeneration (Chen and Strickland,
Cell
, 91, 917-25 (1997)), kainic acid challenged neurons secrete tPA. This initiates a cascade of proteolytic events beginning with conversion of plasminogen to plasmin and ending with degradation of laminin and subsequent death of neurons. Plasmin is a known activator of MMP-9 which could be part of this proteolytic cascade resulting in the eventual destruction of neurons.
In PC12 cells, laminin or specific laminin peptides are capable to stimulating MMP secretion and this mechanism is linked to laminin-mediated neurite outgrowth (Weeks et al.,
Exp. Cell Res
., 243, 375-82 (1998)). There has been a suggestion that these specific laminin sites may only be exposed in the basement membrane as observed in AD (Kibby et al.,
Proc. Nat. Acad. Sci
., 90, 10150-3 (1993)). Further deposition of A&bgr; could be nucleated by these laminin fragments which are found in neuritic plaques. Therefore, interfering with degradation of laminin could have the outcome of preserving the ECM, enhancing neuronal survival, and eliminating at least one protein which may act as a seed for nucleation of A&bgr;.
Elevated expression of MMP-9 and MMP-2 has also been documented in stroke, MS and ALS. After focal ischemia in humans, MMP-9 is markedly elevated in the infarcted tissue at two days post-infarction and remained elevated for months. Increases in MMP-2 were subtle at 2-5 days and like MMP-9, remained marked and significant for months (Clark et al.,
Neuroscience Letters
, 238, 53-6 (1997)). Analysis of brain and spinal cord samples from ALS patients identified major bands of enzyme activity as MMP-2 and MMP-9; MMP-2 in astrocytes and MMP-9 in pyramidal neurons of the motor cortex and motor neurons of the spinal cord. Increases in MMP-9 were observed in ALS frontal and occipital cortices and spinal cord versus control samples. The high level of MMP-9 and its possible release at the synapse may destroy the structural integrity of the surrounding matrix thereby contributing to the pathogenesis of ALS. (Lim et al.,
J. Neurochemistry
, 67, 251-9 (1996)). MMP-9 is elevated in CSF of MS patients and is detected by immunochemistry in active and chronic lesions. In autopsied samples from normal brain, MMP-like immunoreactivity (MMP-1, -2, -3 and -9) is localized to microglia and astrocytes. In MS patient samples, MMP expression is up-regulated in these glial cells and also in perivascular macrophages that are present in active brain lesion. (Chandler et al.,
J. Neuroimmunology
, 72, 155-61 (1997); Liedtke et al.,
Annals of Neurology
, 44, 35-46 (1998).)
In addition to the foregoing, MMP's have been associated with neuronal degeneration in a number of animal models. These models can be used in an MMP inhibitor program to track inhibitor activity and predict pre-clinical efficacy. After focal ischemia in rats, MMP-9 was shown to increase in the infarcted area during the first day (Rosenberg et al.,
J. Cerebral Blood Flow
&
Metabolism
, 16, 360-6, (1996)). MMP-2 remained the same until 5 days after injury when it increased significantly. This time course of induction is very similar to that seen by
Sahagan Barbara G.
Villalobos Anabella
Criares Theodore J.
Ginsburg Paul H.
Myers Jeffrey N.
Pfizer Inc
Richardson Peter C.
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