Remedies for motor dysfunction and GAPDH expression inhibitors

Details Remedies for motor dysfunction and GAPDH expression inhibitors Remedies for motor dysfunction and GAPDH expression inhibitors

2001-04-02

2002-02-19

Henley, III, Raymond (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

Reexamination Certificate

active

06348488

ABSTRACT:

TECHNICAL FIELD
The present invention relates to:
1) A remedy for motor dysfunction, comprising as an active ingredient N-[3-[N-(4-chlorophenylmethyl)carbamoyl]propanoyl]-L-prolinal,
2) A remedy for a disease caused by overexpression of glyceraldehyde-3-phosphate dehydrogenase (hereinafter, abbreviated as “GAPDH”), comprising the same compound as above as an active ingredient, and
3) An inhibitor for apoptosis containing the same compound as above as an active ingredient.
BACKGROUND ART
Prolyl endopeptidase (post-proline cleaving enzyme; abbreviated as “PPCE”) is an enzyme that hydrolyzes many proline-containing peptide hormones to inactivate them. Examples of proline-containing peptide hormones include vasopressin, oxytocin, substance P, neurotensin, bradykinin, angiotensin II, thyroid gland stimulating hormone release factor (TRH), etc. Among these neuropeptides, particularly vasopressin relates to memory and learning. Therefore, its inhibition of the enzyme is considered to be useful for the therapy of cognition failure, so that N-[3-[N-(4-chlorophenylmethyl)carbamoyl]propanoyl]-L-prolinal has been developed as an anti-dementia drug.
N-[3-[N-(4-chlorophenylmethyl)carbamoyl]propanoyl]-L-prolinal is the compound described in Example 2(f) of Japanese Patent Publication 6-4583 (European Patent No. 2681190). Japanese Patent Publication 6-4583 describes that proline derivatives inclusive of this compound inhibit PPCE and hence they are useful in the prevention and/or therapy of amnesia.
Previously, the present inventors have reported that rat cerebellar granule cells (CGC) when subcultured in the presence of KCl (25 mM) without exchanging with fresh culture medium or supplementing glucose caused apoptosis suddenly after 2 weeks or more from the initiation of the culture (Japanese Patent Application Laid-open No. 8-92127).
Since it is inhibited by N-methyl-D-aspartate (NMDA) receptor antagonist and antioxidants, the age-induced apoptosis of CGC is considered to be attributable to overstimulation of NMDA receptor by glutamic acid that is released endogenously or to subsequently formed activated oxygen species.
Further, it has also been elucidated that overexpression of glyceraldehydes-3-phosphate dehydrogenase (GAPDH) (a typical glycolytic enzyme that has many non-glycolytic functions) is closely connected with the age-induced apoptosis of CGC.
Inhibition of mRNA of GAPDH with GAPDH anti-sense oligonucleotide results in inhibition of the overexpression of proteins, which in turn inhibits age-induced apoptosis of neuronal cells. Therefore, inhibition of expression of GAPDH mRNA or GAPDH protein enables inhibition of apoptosis.
GAPDH is also known to selectively bind to gene products (particularly triplet repeat proteins) that are causative proteins in other neurodegenerative diseases (Burke et al., 1996; Koshy et al., 1996). The gene products include huntingtin in Huntington's disease, atrophin in dentate nucleus red nucleus pale globe Luys' body atrophy (DRPLA), ataxin in inherited spine cerebellum degeneration (SCA-1), ataxin-3 in Machado-Joseph's disease, androgen receptor in spino-bulbar muscular atrophy (SBMA), etc. Accordingly, it is considered that GAPDH would play some role in these diseases.
DISCLOSURE OF THE INVENTION
The present invention relates to:
1) A remedy for motor dysfunction, comprising as an active ingredient N-[3-[N-(4-chlorophenylmethyl)carbamoyl]propanoyl]-L-prolinal,
2) A remedy for a disease caused by the overexpression of GAPDH, comprising the same compound as above as an active ingredient, and
3) An inhibitor for apoptosis comprising the same compound as above as an active ingredient.
The present inventors have found that N-[3-[N-(4-chlorophenylmethyl)carbamoyl]propanoyl]-L-prolinal hitherto known as a PPCE inhibitor is effective to motor dysfunction model of a neuropathic type and improves the disorder significantly, thus having completed the present invention.
Also, the present inventors have additionally found that N-[3-[N-(4-chlorophenylmethyl)carbamoyl]propanoyl]-L-prolinal inhibits the overexpression of GAPDH and exhibits potent and sustained inhibitory action against age-induced apoptosis. N-[3-[N-(4-chlorophenylmethyl)carbamoyl]propanoyl]-L-prolinal inhibits the induction of mRNA of GAPDH to inhibit the expression of GAPDH protein, thereby inhibiting apoptosis.
These facts cannot be explained by the inhibitory action of prolyl endopeptidase (EC3.4.21.26) of N-[3-[N-(4-chlorophenylmethyl)carbamoyl]propanoyl]-L-prolinal and indicate new adaptation. In fact, no variation of PPCE activity is observed in the process of age-induced apoptosis, so that PPCE is not considered to participate in the process. Further, in the age-induced apoptosis of CGC, N-[3-[N-(4-chlorophenylmethyl)carbamoyl]propanoyl]-L-prolinal gave no influence on 30 types or more of surface receptors inclusive of overactivated NMDA receptors.


REFERENCES:
patent: 4956380 (1990-09-01), Toda et al.
patent: 235162 (1992-08-01), None
International Search Report dated Dec. 14, 1999 for PCT/JP99/05414.

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