Use of a compound with affinity for the mitochondrial...

Details Use of a compound with affinity for the mitochondrial... Use of a compound with affinity for the mitochondrial...

1999-06-14

2001-11-20

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S144000

Reexamination Certificate

active

06319931

ABSTRACT:

The present invention relates in particular to a combination product comprising at least one compound with affinity for the mitochondrial benzodiazepine receptor, and to at least one apoptosis-inducing agent for simultaneous or separate use or for use spread out over time, which is intended for the treatment of cancer. Another aspect of the present invention relates to the use of the said compound and/or of the said combination product for the manufacture of a medicinal product intended to facilitate the induction of apoptosis.
The methods currently used in the treatment of cancer are mainly radiotherapy and chemotherapy. These techniques consist in eradicating the tumor cells identified by means of localized irradiations or by means of pharmacological inducers of cell death. However, these therapeutic approaches are not specific to the tumor cells alone. Indeed, the neighboring tissues are also eradicated and very high toxicity is observed. Considering that the natural programs of cell death (or apoptosis) and senescence no longer function in tumor cells, one approach for treating cancer might lie in re-establishing these programs.
In general, apoptosis is characterized by three phases: an initiation phase in which the various death stimuli take so-called “private” pathways to converge on a common effector phase, which leads finally to the degradation phase characterized by the characteristic biochemical symptoms of cell death. The effector phase is carried out by the mitochondrial permeability transition pore, which is the true sensor of cell death since its open or closed conformations determine the fate of the cells. These different conformations can be induced by many ligands for the components of this permeability transition pore.
The mitochondrial permeability transition pore, commonly known as the mega-channel or multi-conductance channel, participates in regulating the level of calcium in the matrix, the pH and the transmembrane potential (&Dgr;&PSgr;
m
) in the mitochondria. This pore (PT) thus functions as a channel which is dependent on Ca
2+
, the voltage, the pH and the redox potential with several levels of conductance and little selectivity with respect to the ions (Zoratti et al. 1995, Kinnally et al. 1996, Bernardi et al. 1996, and Ichas et al. 1997). Recently, it has been demonstrated that opening of tile PT pore, which is regulated by Bcl-2, is a critical event in the process leading to apoptosis (Kroemer et al. 1997a and 1997b). Opening of the PT pore allows dissipation of the mitochondrial internal transmembrane potential (&Dgr;&PSgr;
m
), the consequence of which is to disrupt the integrity of the outer membrane, leading to the release of mitochondrial intermembrane proteins (Zamzami et al. 1996, Susin et al. 1997a, Kantrow et al. 1997 and Ellerby et al. 1997). In point of fact, the release of intramembrane proteins, such as cytochrome c, and/or the dissipation of the &Dgr;&PSgr;
m
are common elements of the early phase of apoptosis (Kroemer et al. 1997a and 1997b, Liu et al. 1996, Kluck et al. 1997, Yang 1997 and Susin et al. 1997b). Depending on the experimental system and the cell type, an increase in the volume of the matrix causes either a physical disruption of the outer mitochondrial membrane and then dissipation of the &Dgr;&PSgr;
m
(Kluck et al. 1997, Yang et al. 1997 and Vander Heiden et al. 1997) or a disruption of the outer membrane and simultaneous dissipation of the &Dgr;&PSgr;
m
of the inner membrane (Zamzami et al. 1996 and Susin et al. 1996a). Regarding the theoretical aspect, the authors mentioned above have postulated that the increase in the volume of the matrix, which precedes the reduction of the &Dgr;&PSgr;
m
, might be controlled by opening the PT pore. In this sense, the PT pore can operate both at a level of low and reversible conductance (which would give rise to an influx of ions and water into the mitochondrial matrix), and at a level of high and irreversible conductance (which would lead to disruption of the &Dgr;&PSgr;
m
).
The PT pore is a multiprotein complex formed at the site of contact between the inner and outer mitochondrial membranes. Co-localization of the PT pore and of the Bcl-2 oncoprotein is observed (De Jong et al. 1994). The exact molecular composition of this pore remains an enigma. However, it is known that proteins of the cytosol (hexokinase), of the outer membrane (mitochondrial benzodiazepine receptor [mBzR], mitochondrial porin, commonly referred to as the voltage-dependent anion channel), the intermembrane space (creatine kinase), the inner membrane (adenine nucleotide translocator, ANT) and the matrix (cyclophilin D) are involved in the formation of the PT pore and/or in its regulation (Zoratti et al. 1995, Beutner et al. 1996, McEnery 1992, Kinnally et al. 1993, O'Gorman 1997). The PT pore is regulated by multiple endogenous effectors, which is in accordance with its complex composite architecture. Among these effectors are the local ions and the pH gradient, ADP/ATP, NADPH and the molecules involved in transduction of the apoptotic signal, such as Ca
2+
or oxygen-reactive species. Thus, some of the subunits of the PT pore night constitute pharmacological targets for modulating apoptosis.
Compounds belonging to the isoquinolinecarboxamide family have been described in U.S. Pat. No. 4,801,595 as being useful for the treatment of hypertension, In this family, PK11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide) is known as being a prototypic antagonist ligand for the peripheral benzodiazepine receptor mBzR (Ripond et al. 1991 and Joseph-Liauzun et al. 1997). More particularly, WO 93/11771 relates to the use of molecules such as PK11195 for the treatment of diseases of the central nervous system, in particular trauma.
Now, surprisingly, certain compounds with affinity for the mitochondrial benzodiazepine receptor allow opening of the mitochondrial permeability transition pore, and the experiments which have led to the present invention demonstrate that compounds of formula I, II, III, IV, and V in particular facilitates cell death.
Cancer therapy currently consists in using radiotherapy, chemotherapy or a combination of these. These two methods have harmful side effects which are very poorly tolerated by the patients. Thus, the use of pharmacological agents designed to increase the susceptibility of tumor cells to apoptosis induction is very advantageous, since it allows the use of lower doses of chemotherapy or radiotherapy products, thereby minimizing their side effects. Components with strong affinity for the PT pore subunits, mentioned above, are the subject of the present invention since they facilitate apoptosis and thus allow the use of lower doses of products with strong side effects. This also makes it possible to improve the efficacy of certain treatments.
Thus, no document of the prior art either discloses or suggests the present invention as described below.
DESCRIPTION OF THE INVENTION
Thus, the present invention relates to a combination product comprising at least one compound with affinity for the mitochondrial benzodiazepine receptor, and to at least one apoptosis-inducing agent for simultaneous or separate use or for use spread out over time, which is intended for the treatment of cancer.
The term cancer is used in a broad sense which includes any neoplasia (for example cancers, sarcomas, lymphomas and leukemias).
The said compound is selected from several families of molecules with affinity for the mitochondrial (peripheral) benzodiazepine receptor, preferably from the families of general formulae I, II, III, IV and V described below.
In the isoquinoline family, the molecules chosen in particular are of general formula I:
in which
R1 is a linear or branched C1-C6 lower alkyl group,
R2 is a linear or branched C1-C6 lower alkyl group,
R3 is a halogen atom such as Cl, F, Br or I,
and R4 is a hydrogen or halogen atom,
the groups R1, R2, R3 and R4 being chosen independently of each other.
Advantageously, the said compound is PK111

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