The antagonist ligand raror agonist-ligand raras an inhibitor of apoptosis

 

(57) Abstract:

The invention relates to medicine, specifically to pharmacology. A new tool for inhibiting apoptosis in a cell population of T-lymphocytes. The tool is an agonist specific to the retinoic acid receptors RAR-alpha (in particular, 4-((5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido)benzoic acid), or 4-[7-(1-substituted)-6-methoxyethoxy-toxi-2-naphthyl]benzoic acid. The tool is intended for treatment of diseases associated with the excessive rate of apoptosis, including immunodeficiency syndrome caused by the human immunodeficiency virus (HIV) or transplant rejection. The invention expands the Arsenal of the declared destination. 4 C.p. f-crystals, 4 PL.

The present invention relates to the use of special retinoids to obtain a pharmaceutical composition intended for reducing the speed of development of apoptosis.

Cell death involves the mechanism of the two types. The first of them, which is the classic type, called necrosis. Morphologically necrosis is characterized by swelling of the mitochondria and cytoplasm and deformation of cell nuclei, after which there is Bassigny and random development. The tissue necrosis is usually associated with cells that are subjected to physical trauma exposure or chemical poisoning.

Another form of cell death called apoptosis (Kegg, J. F. R. and Wyllie, A. H., Br.J.Cancer, 265, 239 (1972); however, it should be noted that in contrast to necrosis, apoptosis does not cause any inflammation. It is known that apoptosis is developing in a variety of physiological conditions. Apoptosis is a highly selective form of cell suicide, which is characterized by marked morphological and biochemical phenomena. For example, the observed phenomena, to which, in particular, condensation of chromatin, can be related or not related to their endonuclease activity, formation of apoptotic bodies and fragmentation of deoxyribonucleic acid (DNA) through the activation of endonucleases in DNA fragments by size of 180-200 base pairs (such fragments can be observed in agarose gel electrophoresis).

Apoptosis can be considered as programmed cell death, is included in the development, differentiation and tissue regeneration. We can also assume that the differentiation, growth and maturation of cells closely the current also associated with the phenomenon of apoptosis. It should be noted that in a healthy person, all these things are in balance.

In the field of medicine in some pathological situations, there is a modified, if not misaligned, the mechanism of apoptosis or apoptotic mechanism, which does not provide for the deregulation of other biological phenomena in order to achieve equilibrium. So, it is reported that the intentional modulation of apoptosis by induction or suppression can treat many of these diseases that are associated with insufficient speed of apoptosis, as in the case of cancer, or autoimmune diseases or allergies, or, on the contrary, such diseases that are associated with excessive rate of apoptosis, as in the case of immunologic deficiency syndrome under the influence of human immunodeficiency virus (HIV), neurodegenerative diseases (Alzheimer's disease) or excessive damage that occurs during myocardial infarction.

The literature describes a number of inhibitors of apoptosis, such as cycloheximide, cyclosporine and some interleukins.

In the field of retinoids known that t is depending on the nature of the treated cells) differentiation and proliferation of many types of normal or transformed cells. For example, retinoic acid inhibits differentiation of these epithelial cells as epidermal keratinocytes. It also inhibits proliferation of many transdermal cells such as melanoma cells. Such effects on the proliferation and differentiation can have cells of the same type at the same time, as it takes place, for example, in the case of promyelocytes person (cells HL-60); thus, it is known that proliferation of these cells inhibited by all-TRANS retinoic acid and that at the same time, induced their differentiation into granulocytes and their apoptosis.

Generally speaking, it is known that all-TRANS retinoic acid affects the differentiation and proliferation of cells by interacting with receptors of the cells, referred to as RAR (retinoic acid receptors), which are present in cell nuclei. To date, identified three subtypes of RAR receptors, which are classified as RAR, RAR, and RAR, respectively. After binding to a ligand (for example, all-TRANS retinoic acid), these receptors interact with specific reactive elements (RAREs) in the promoter region of genes that are regulated by retinoic acid is generated as RXR. Natural RXR ligand is 9-CIS-retinoic acid. Such RXR considered the main regulatory proteins, as they interact, forming heterodimer, like RAR, with other members of the superfamily of steroid/thyroid receptors such as the vitamin D3 receptor (VDR), triiodothyronine receptor (TR) and PPAR (receptors activated by proliferation peroxisome). In addition, RXR able to interact with specific reactive elements (RXRE) in the form of homodimers. These complex interactions, as well as the existence of numerous RAR and RXR receptors, which are differently expressed depending on the type of tissue and cells due to the pleiotropic effects of retinoids in almost all cells.

In modern literature describes many synthetic structural analogs of all-TRANS retinoic acid or 9-CIS-retinoic acid, which is usually referred to as "retinoids". Some of these molecules able to specifically bind and activate RAR or, on the other hand, RXR. In addition, some analogues can bind and activate specific subtype of the RAR receptor (or ). Finally, other analogues do not show any particular selective activity of acid activates RAR and RXR at the same time, showing the minimum selectivity in relation to a specific receptor (non-specific agonist ligand), whereas all-TRANS-retinoic acid selectively activates RAR (RAR-specific agonist-ligands), which includes all subtypes. Speaking in General and qualitatively, we can say that the substance (or ligand) has specificity with respect to this family of receptors (or, respectively, in relation to a specific receptor of this family) in the case if the substance has an affinity for all receptors of this family (or, respectively, in relation to a specific receptor of this family), which is higher than the affinity, which is manifested in all receptors of any other family (or, respectively, in relation to all other receptors of this family or another family).

There is a message stating that 9-CIS-retinoic acid and all-TRANS-retinoic acid are modulators of apoptosis (i.e., an activator or inhibitor of apoptosis, depending on the specific cell type) and 9-CIS-retinoic acid is more active substance of these two modulators, and the explanation of this phenomenon may be oewoi acid, which activates only RAR.

In the light of what has been said above, it is obvious that there is some interest in the development of new modulators of apoptosis.

In this respect the authors of this application has failed to establish that the agonist-ligand specific for the receptor type RAR, or antagonists, ligands that are specific for receptors of type RAR, are excellent inhibitors of apoptosis in cells of various types, mainly in thymocytes, in cases where the cause apoptosis using receptor type RAR - or T-cell receptor.

Thus, the present invention relates to the use of at least one ligand selected from the agonist-ligand specific for the receptor type RAR-antagonist ligand which is specific for receptors of type RAR, upon receipt of a pharmaceutical composition intended for reducing the rate of apoptosis in at least one cell population. More specifically, this population of cells corresponds to the cells in which apoptosis can be regulated by induction and/or inhibition using receptor type RAR and/or RAR or apoptosis can be induced via receptors of T cells.

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Under the agonist-ligand-specific receptor type RR-, according to the invention is meant any agonist-ligand with a dissociation constant with the receptor type RAR-at least 10 times smaller dissociation constants with receptor type RAR, and which causes differentiation of F9 cells.

Under the antagonist is a ligand-specific receptor type RAR, according to the invention refers to any ligand with a dissociation constant with the receptor type RAR-at least 10 times lower than its dissociation constants with receptor type RAR, and which does not cause differentiation of F9 cells.

For example, it is known that all-TRANS retinoic acid and some of its analogues capable of inducing differentiation of embryonic cells teratocarcinoma mouse (cell F9); therefore, these substances are considered as agonists of RAR receptors. The secretion of plasminogen activator accompanying differentiation, is an indicator of the biological reactions of F9 cells to retinoids (Skin pharmacol., 1990, 3: pp. 256-267).

Dissociation constants determined by means of tests, the standard for professionals in this field. Such tests, mainly described the, 'arcel Dekker Inc., edited by Maria A. Livrea and Lester Parker; (2) "Synthetic Retinoids: Receptor selectivity values and Biological Activity in Skin Pharmacol., Basel, Karger, 1993, Volume 5, pp.117-127; (3) "Selective Synthetic Ligands for Human Nuclear Retinoic Acid Receptors in Skin Pharmacology, 1992, Vol.5, pp.57-65; (4) "Identification of Synthetic Retinoids with selectivity values for Human Nuclear Retinoic Acid Receptor-" in Biochemical and Biophysical Research Communications, Vol.186, 2, July 1992, pp.977-983; (5) "Selective High Affinity RAR or RAR Retinoic Acid Receptor Ligands" in Mol.Pharmacol., Vol.40, pp.556-562.

Other characteristics, aspects, objectives and advantages of the invention will become even clearer from reading the following description and specific examples, which are presented for purposes of illustration and in no way are of a restrictive nature.

Agonists-ligands having specificity receptor type RAR and which should be mentioned first of all, are 4-((5,6,1,8-tetrahydro-5,5,8,8-tet-rameter-2-naphthalenyl)carboxamido)benzoic acid, 4-((5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene)carbarnoyl)benzoic acid and 2-hydroxy-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-carboxamido)benzoic acid.

Among the agonists-ligands having specificity receptor type RAR, according to the invention the advantage of using given at least one agonist-lifesocial receptor type RAR, for example, such as 4-((5,6,7,8-tetrahydro-5,5,8,8-Tetra-methyl-2-naphthalenyl)carboxamido)benzoic acid and 2-hydroxy-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen)-2-CT-oxamide)benzoic acid.

Agonists-ligands specific for receptors of type RAR and want to mention, mainly, are 2-hydroxy-4-[7-(1-substituted)-6-benzyloxy-2-naphthyl] benzoic acid, 2-hydroxy-4-[7-(1-substituted)-6-hexyloxy-2-naphthyl] benzoic acid, 4-[7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl] benzoic acid, 5-[7-(1-substituted)-6-benzyloxy-2-naphthyl] -2-thiencarbazone acid, 4-[7-(1-substituted)-6-benzyloxy-2-naphthyl] benzoic acid, 4-[7-(1-substituted)-6-benzyloxycarbonyl-2-naphthyl] benzoic acid, 2-hydroxy-4-[7-(1-substituted)-6-(4-terbisil)oxy-2-naphthyl] benzoic acid, 4-[7-(1-substituted)-6-heptyloxy-2-naphthyl]benzoic acid, 6-[7-(1-substituted)-6-methoxyethoxy-methoxy-2-naphthyl]nicotinic acid, 2-hydroxy-4-[7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl] benzoic acid, 2-chloro-4-[7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl] benzoic acid, 4-[7-(1-substituted)-6-methoxybenzyloxy-2-naphthyl]benzoic acid, 4-[7-(1-substituted)-6-methoxyethoxymethyl-2-naphthyl]benzoic acid, 4-[7-(1-substituted)-6-methoxyethoxy>Of the antagonists, ligands, with the specificity of receptor-type RAR, in the present invention preference is given to using at least one antagonist of the ligand with a dissociation constant with the receptor type RAR-at least 20 times lower than its dissociation constant with receptor type RAR-, such as 4-[7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl]benzoic acid.

Thus, the composition according to the present invention can be applied, if you want to decrease the speed of the development of apoptosis in the event that at least one population of cells. More specifically, the population of cells corresponds to the cells in which apoptosis can be regulated by induction and/or inhibition using receptor type RAR and/or RAR, or in which apoptosis can be regulated by induction using receptors of T cells, and therefore, in particular, takes place in the cell populations, which contain receptor type RAR and/or RAR, or receptors of T cells, for example, those that are derived from the thymus (thymus gland), which means that all three types of receptors.

Thus, the reduction in the rate of development of apoptosis may ukazatel may be the result of genetic or acquired conditions of the patient, for which it is desirable the use of pharmaceutical compositions. Such genetic or acquired condition favorable for the accumulation of signals that induce apoptosis, or reduce the threshold induction of apoptosis by these signals.

As examples of diseases or disorders associated with an excess rate of apoptosis, it should be noted immunodeficiency syndrome caused by the human immunodeficiency virus (HIV), neurodegenerative diseases, myelodysplastic syndromes (such as aplastic anemia), ischemic syndromes (e.g., myocardial infarction), diseases of the liver caused by toxins (such as alcohol), alopecia, skin damage due to UV exposure, lichen planus, skin atrophy, cataracts and rejection of different grafts.

So, more specific examples include neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophy lateral sclerosis and other related degeneration of the brain, such as disease Creutzfeld-Jakob.

The composition according to the invention can be applied enterline, parenteral, topical or ocular route. Preferably, such pharmaceutics is SS="ptx2">

For use by enteral composition, especially a pharmaceutical composition, may be in the form of tablets, hard gelatin capsules, coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles, allows for controlled selection. In the case of parenteral administration, the composition can be used in the form of solutions or suspensions for infusion or injection.

The ligands are selected from agonists of ligands having specificity to the receptor type RAR, and antagonists of ligands, which possess a specificity of receptor-type RAR and use according to the invention, usually used in a daily dose from about 0.01 mg/kg to 100 mg/kg body weight, once or up to three doses per day.

The local application of the pharmaceutical composition according to the invention is best suited for the treatment of skin and mucosa and can be used in the form of ointments, creams, molotkovyh preparations, lipsticks, powders, impregnated buffers, solutions, gels, spree, lotions or suspensions. They can also be in the form of microspheres or nanospheres or lipid or polymeric Wei local application of the composition may be anhydrous, and in the form of an aqueous solution.

When the eye using a composition according to the invention is mainly used in the form of eye lotions.

The ligands are selected from agonists of ligand-specific receptor type RAR, and antagonists of ligand-specific receptor type RAR, local and ocular applications are used in concentrations of 0.001-10 wt. %, preferably 0.1 to 1 wt.%, calculated on the total weight of the composition.

Of course, the above compositions can additionally contain inert or even pharmacodynamically active additives or combinations of these additives, in particular wetting agents, depigmenting agents, such as hydroquinone, azelaic acid, caffeic acid or kojic acid; softening means; moisturizing agents such as glycerol, PEG 400, thiomorpholine and its derivatives or even urea; antiseborrheic agents or anti-acne agents such as S-carboxymethylcysteine, S-benzylsuccinic and their salts or derivatives, or benzoyl peroxide; antifungal agents, such as ketoconazole or polymethylene-4,5-ittia-solidin-3-ones; antibacterial agents; carotenoids and, in particular,- carotene; such protelos the new acid, their esters and amides.

These compositions can also contain substances that improve the smell, these protecting agents, as esters with parahydroxybenzoic acid, stabilizing agents, humidity regulating agents, pH regulating agents, agents for modifying the osmotic pressure, emulsifying agents, filters, UV-a and UV-b, antioxidants such as tocopherol, butylhydroxyanisole or equivalent.

Typically, for a specialist in this area should be clear that when you add in the composition of the possible connections are selected so that the advantages inherent in the present invention, is not changed or changed only slightly.

Below are some examples of the present invention, and they are presented only to illustrate the invention and does not limit.

EXAMPLE 1.

This example demonstrates the in vitro effectiveness of RAR - specific antagonist is a ligand as an inhibitor of apoptosis, when apoptosis is induced by other retinoids.

Cultivation and receiving cells.

Suspensions of thymocytes were obtained from the thymus gland untreated mice male NMRI in free serum (Gibco), containing 2 mm glutamine, 100 units penicillin and 100 μg streptomycin/ml, the Thymocytes were washed, then diluted this medium to obtain a final concentration of 107cells/ml and incubated at 37oWith in a humidified incubator in an atmosphere containing 5% CO2and 95% air. Cell death was estimated by the absorption Trypanosoma blue.

Qualitative and quantitative analysis of DNA.

The thymocytes were incubated in 24 wells in the presence of various test compounds. After 6 hours incubation, 0.8 ml volumes of cell suspension was subjected to lysis by adding 0.7 ml lisanova buffer containing 0.5% (vol. /about.) Triton X-100, 10 mm Tris, 20 mm EDTA, pH 8.0, after which they were subjected to centrifugation (13000g, 15 minutes).

- Quantitative analysis of DNA: DNA contained in the supernatant (fragments) and sediment (intact chromatin) was besieged by an equal volume of 10% trichloroacetic acid, resuspendable in 5% trichloroacetic acid and then quantitatively determined using diphenylamine reagent (Burton K., (1956) Biochem.J., 62, 315-322).

- Qualitative analysis of DNA: parallel supernatant precipitously overnight in ethanol containing 0.15 mm NaCl. The residue was re-dissolved in buffer, with the system of equal volume of phenol and chloroform/isoamyl alcohol (24/1); then DNA was besieged in ethanol prior to electrophoresis for 3 hours at 60 V in a 1.8% agarose gel. Then the DNA fragments were visualized by UV light after staining the gel ethidiumbromid. The obtained gels were given a picture of the bands of DNA fragments consisting of 180-200 base pairs and is typical for induction of apoptosis. During the experiments, the degree of fragmentation is correlated with the number of dead cells, painted Trifanova blue.

The results of the quantitative analysis are presented in table. 1.

The percentage of DNA fragments that are listed in the table. 1, corresponds to the difference between the percentage of DNA fragments obtained in the treated thymocytes, and the percentage of DNA fragments obtained in the medium of untreated thymocytes (the basic rate of apoptosis for these thymocytes).

From the above table. 1 it is clear that apoptosis induced by ATRA, 9-CIS-RA and CD437, inhibited CD2665, which is an antagonist of a ligand specific for the receptor type RAR.

EXAMPLE 2.

This example demonstrates the in vitro efficacy RAR--specific agonist ligand as an inhibitor of apoptosis in the case, when apoptosis was induced by others who took the nature of the tested ligands and their concentration.

So, CD437 (6-3-(1-substituted)-4-hydroxyphenyl)-2-naftaniel acid), used at the same concentration, were incubated with thymocytes in the presence of various concentrations of CD336 (4-((5,6,7,8-tetrahydro-5,5,8,8-Tetra-methyl-2-naphthalenyl)carboxamido)benzoic acid).

In table. 2 presents the obtained results.

The percentage of DNA fragments, specified in this table corresponds to the difference between the percentage of DNA fragments obtained in the treated thymocytes, and the percentage content of the DNA fragments obtained in untreated thymocytes (basic rate of apoptosis for these thymocytes).

From the data table. 2 it is clear that apoptosis, which is induced by the action of CD437, which is the agonist is a ligand having specificity receptor type RAR, subject to inhibition dose-dependent manner under the action of CD336, which is the agonist-ligand with specificity receptor type RAR.

EXAMPLE 3.

This example illustrates the effectiveness RAR--specific agonist ligand in vitro as an inhibitor of apoptosis in the case when apoptosis is induced by an activating receptor of T cells.

Use the concentrations.

It is known that T cells differentiate in the thymus gland in Mature T-lymphocytes. During the differentiation of T-cells proliferate and acquire receptors inherent in T-cells. Cells that Express potentially self-reactive cellular receptors which interact with cells representing Athen, undergo apoptosis (negative selection) (Smith al. , (1989) Nature, 337, 181-184). Such selection can be simulated in vitro by stimulation of the CD3 molecules, which is associated with the receptor of T cells, as a result of simultaneous add verbatimwrite and CA++ion-Faure (with Iseki al., (1991), J. Inununol., 147, 4286-4292).

Formultimedia (5 ng/ml) and Ca++ionophor (0.5 µm) were incubated with thymocytes in the absence or in the presence of various concentrations of CD336 (4-((5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido)benzoic acid).

The results obtained are presented in table. 3.

In table. 3 R+denotes formultimedia (5 ng/ml) and CA++ionophor (0.5 µm).

The percentage of DNA fragments in the following table corresponds to the difference between the percentage of DNA fragments obtained from untreated thymocytes, and percentage of DNA-FR is Thus in table. 3 clearly shows that the apoptosis induced by the action of R+, inhibited dose-dependent manner under the action of CD336, representing agonist-ligand-specific receptor type RAR.

EXAMPLE 4.

This experiment demonstrates the effectiveness RAR--specific antagonist ligand in vivo as an inhibitor of apoptosis, in the case when apoptosis is induced by RAR--specific agonist-ligand.

Used of male mice NMRI at the age of 4 weeks (supplied LATI Gdllo, Hungary). To induce apoptosis in the thymus such mice-males produced a single intraperitoneal injection of 6-3-(1-substituted)-4-hydroxyphenyl)-2-naftaniel acid (0.5 mg), which was dissolved in 40 μl of DMSO and 0.5 ml of 20% ethanol. In order to observe the effect of inhibition of apoptosis, which is induced in the thymus agonist is a ligand that is specific for RAR-, mice-males produced a single intraperitoneal injection of a mixture of 0.5 mg 6-3-(1-substituted)-4-hydroxyphenyl)-2-naftaniel acid (CD437) and 5 mg of 4-[7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl]benzoic acid (CD2665), and this mixture was dissolved in 40 μl of DMSO and 0.5 ml of 20% ethanol. In control mice-males produced a single intraperitoneal injection is written above.

At 48 hours after treatment was determined by the weight of the thymus and the results obtained are summarized in table. 4.

Thus, the involution of the thymus was observed after treatment of CD437 separately and significant changes were not observed under the action of CD2665, whereas the combination CD2665 and CD437 leads to involution of the thymus, which is much less pronounced than under the action of only one CD437.

1. The use of agonists that are specific to the retinoic acid receptors RAR-alpha, or 4-[7-(1-substituted)-6-methoxyethoxyethoxy-2-naphthyl] benzoic acid as a means for inhibiting apoptosis in a cell population of T-lymphocytes.

2. Application under item 1, wherein the agonist is a ligand-specific receptor RAR-alpha, has a dissociation constant with the receptors of the RAR-alpha, which is at least 20 times smaller than its dissociation constant with receptor type RAR-gamma.

3. Use PP.1 and 2, characterized in that the agonist-ligand-specific receptor type RAR-alpha, is a 4-((5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido)benzoic acid.

4. The use according to any one of the preceding paragraphs, characterized in that the means p is tion by p. 4, characterized in that the said diseases associated with the excessive rate of apoptosis is selected from immunodeficiency syndrome caused by the human immunodeficiency virus (HIV) or transplant rejection.

 

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