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  Pharmaceutical Patents  

 

Title:  Tissue-specific transporter inhibitor
United States Patent: 
7,420,029
Issued: 
September 2, 2008

Inventors: 
Tsuji; Akira (Kanazawa, JP), Tamai; Ikumi (Kanazawa, JP), Sai; Yoshimichi (Kanazawa, JP), Yui; Noubuhiko (Ishikawa, JP), Oya; Toru (Ishikawa, JP), Miyamoto; Ken-ichi (Tokushima, JP)
Assignee: 
Japan Science and Technology Agency (Saitama, JP)
Appl
. No.: 
10/742,335
Filed: 
December 19, 2003


 

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Abstract

The present invention is to provide a tissue-specific transporter inhibitor which is not absorbed through the digestive tract and can prevent deterioration in the QOL of a patient caused by diet therapy, and a therapeutic drug for tissue dysfunction diseases and a therapeutic drug for suppressing the progress of chronic renal failure containing the inhibitor as an active ingredient. A tissue-specific transporter inhibitor which is not absorbed through the digestive tract is constructed by introducing a dipeptide which is a ligand of an oligopeptide transporter 1 into a supramolecular structure polyrotaxane wherein its structurally modified active residue is expected to be excellent in the interaction with a transmembrane transporter.

Description of the Invention

FIELD OF THE INVENTION

The present invention relates to a tissue-specific transporter function inhibitor which has both a ligand structure recognized by a tissue-specific transporter and a polymeric molecular structure incapable of passing through a membrane tissue, and a therapeutic drug for tissue dysfunction diseases or a therapeutic drug for suppressing the progress of chronic renal failure containing the tissue-specific transporter function inhibitor as an active ingredient, and the like.

BACKGROUND

Nowadays, the number of dialysis patients are increasing, and it is presumed that the number of such patients will be enormous when taking into account the number of diabetic patients who will be in need of dialysis in the future, and the medical expenses for dialysis is estimated to be well over 1 trillion yen. Considering these situations, preventive medicine that prevents the onset of renal diseases and conservative treatments that prevent the progress of renal failure into dialysis are regarded important. Effective treatments of renal disorders in patients of chronic renal failure have not been established yet, treatments including low protein diet therapy and the administration of antihypertensive drugs such as an ACE inhibitor have been conducted so far (Am. J. Cardiol. 59, 66A-71A, 1987; Am. J. Kidney. 20, 443-57, 1992; BMJ 304, 216-20, 1992; Ann. Intern. Med. 124, 627-32, 1996). The above-mentioned low protein diet therapy is thought to be effective means to suppress the progress of chronic renal failure and is widely conducted currently. However, since dietary restriction contains problems of quality of life (QOL) and compliance of patients, a new therapeutic strategy, for example, suppression of oral protein absorption, is needed. Recently, as a new strategy for the treatment of hyperlipemia, it is reported that biosynthesis of cholesterol is suppressed by inhibiting a bile acid transporter present in the small intestine, and this report draws attention (J. Pharmacol. Exp. Ther. 293, 315-20 2000). Likewise, it is expected that the absorption of proteins through the digestive tract can be suppressed by a specific inhibitor.

The present inventors have reported that proteins taken are digested in the digestive tract to amino acids and oligopeptides and absorbed through the small intestine, and that the absorption is conducted by a specific transporter present in the brush border membrane of a small intestine epithelial cell (Pharm. Res. 13, 963-77, 1996). The digested amino acids mentioned above are transported by multiple transporters, however, the oligopeptides are transported by an oligopeptide transporter such as PEPT 1, and absorbed dipeptide- or tripeptide-specifically (J. Biol. Chem. 270, 6456-63, 1995). As to the absorption of digestive products of proteins in the small intestine, it is known that more peptides are absorbed than amino acids (Gastroenterology 113, 332-40, 1997). Taken together, it is considered that a PEPT 1 inhibitor is capable of suppressing the absorption of proteins in the diet, and is useful for the patients whose QOL is deteriorated due to diet therapy.

Since 1994, PEPT 1 genes have been cloned from small intestines of rabbit, human and rat (J. Biol. Chem. 270, 6456-63, 1995; Nature 368, 563-6, 1994; J. Pharma. Exp. Ther. 275, 1631-7, 1995; Biochim. Biophys. Acta, 1305, 34-8, 1996), and studies for transportation via PEPT 1 have been rapidly developed. The above-mentioned PEPT 1 gene derived from rat small intestine has been cloned for the first time by the present inventors (Biochim. Biophys. Acta, 1305, 34-8, 1996), and revealed to locate in the brush border membrane side of the small intestine epithelial cell by immunohistochemical technique (FEBS Lett. 392, 25-9, 1996). In addition, it is reported that PEPT 1 recognizes and transports compounds such as valacyclovir, an antiviral drug, that does not have a peptide bond in its molecules, as well as compounds having peptide-like structures, for example, .beta.-lactam antibiotics (Pharm. Res. 13, 963-77, 1996; Biochem. Biophys. Res. Commun. 250, 246-51, 1998; J. Clin. Invest. 101, 2761-7, 1998; J. Biol. Chem. 273, 20-2, 1998). As mentioned above, PEPT 1 shows wide range of substrate recognition property, however, its molecular recognition property remains unknown and it is thought that the substrate recognition of PEPT 1 involves not only the recognition of partial structure but also whole molecule. Meanwhile, PEPT 2, which is cloned from the kidney (Biochim. Biophys. Acta, 1235, 461-6, 1995; Biochim. Biophys. Acta, 1280, 173-7, 1996; Proc. Natl. Acad. Sci. USA 93, 284-9, 1996), locates in the brush border membrane side of the epithelial cell in the proximal convoluted tubule of the kidney, and has a substrate recognition property similar to that of PEPT 1, and serves to reabsorbing oligopeptides and peptide-like compounds. The above-mentioned PEPT 1 is known to express in the kidney though it does not contribute very much (Am. J. Physiol. 276, F658-65, 1999). However, PEPT 2 has never been observed to express in the small intestine.

In human, it is reported that bioavailability (BA) of cefadroxil (CDX), a .beta.-lactam antibiotic and a substrate of PEPT 1, is decreased by co administration of cephalexin (CEX), a .beta.-lactam antibiotic similarly recognized by PEPT 1 (Eur. J. Clin. Pharmacol. 41, 179-83, 1991). A mechanism in which AUC (Area Under the plasma concentration Curve) as an index of bioavailability is decreased by CEX includes both the absorption of CDX in the small intestine and the inhibition of reabsorption of CDX in the kidney. The reabsorption through the kidney is conducted mainly via an oligopeptide transporter (PEPT 2), and both compounds are known to be substrates for PEPT 2 (Biochim. Biophys. Acta, 1235, 461-6, 1995). Therefore, it is explicable that the decrease of BA of CDX caused by CEX means that CDX transportation via PEPT 1 and PEPT 2 is inhibited by CEX. Though the effect of the inhibition of PEPT 2 present in the kidney on a living organism is unknown, it seems preferable to limit to a direct inhibition of absorption via PEPT 1 from the viewpoint of diet therapy for chronic renal failure. However, since PEPT 1 and PEPT 2 show very similar substrate recognition properties, it has been presumed to be difficult to develop an inhibitor which specifically recognizes PEPT 1.

The number of dialysis patients due to renal failure are increasing, and it is presumed that the number of such patients will be enormous when taking into account the number of diabetic patients who will be in need of dialysis, and the medical expenses for dialysis is estimated to be well over 1 trillion yen in the future. Under these circumstances, preventive medicine that prevents the onset of renal diseases and conservative treatments that prevent the progress of renal failure into dialysis are important. The object of the present invention is to provide a tissue-specific transporter inhibitor which is not absorbed through the digestive tract and can prevent deterioration in the QOL of patients caused by diet therapy, and a therapeutic drug for tissue dysfunction diseases and a therapeutic drug for suppressing the progress of chronic renal failure containing the inhibitor as an active ingredient.

The present inventors have considered that it is effective to use a PEPT 1 inhibitor which is not absorbed through the digestive tract and is able to avoid recognizing PEPT 2 in order to attain the above-mentioned object, and that PEPT 1 can be selectively inhibited by designing a polymer compound having PEPT 1 recognition property because polymer compounds are not absorbed through the digestive tract in general. Therefore, the present inventors have focused on a supramolecular structure polyrotaxane (PRX) wherein its structurally modified active residue is expected to be excellent in the interaction with a transmembrane transporter, and constructed a compound wherein a dipeptide (Val-Lys) which is a ligand of the PEPT 1 mentioned above is introduced into a supramolecular structure PRX. As a result of intensive study, it has been found that the above-mentioned compound can suppress the absorption of proteins and the progress of chronic renal failure which needs limitation of protein uptake, and thus the present invention has been completed.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to a tissue-specific transporter function inhibitor which has both a ligand structure recognized by a tissue-specific transporter and a polymeric molecular structure incapable of passing through a membrane tissue (paragraph 1), the tissue-specific transporter function inhibitor according to paragraph 1, wherein the polymeric molecular structure incapable of passing through a membrane tissue is a supramolecular structure (paragraph 2), the tissue-specific transporter function inhibitor according to paragraph 2, wherein the supramolecular structure is a rotaxane compound in which a number of circular molecules are penetrated by linear molecules, and both ends of the linear molecules are capped by bulky substituents (paragraph 3), the tissue-specific transporter function inhibitor according to paragraph 3, wherein the circular molecules are cyclodextrins (paragraph 4), the tissue-specific transporter function inhibitor according to paragraph 3 or 4, wherein the linear molecules are polyethyleneglycols (paragraph 5), the tissue-specific transporter function inhibitor according to any one of paragraphs 3 to 5, wherein the bulky substituents are N-benzyloxycarbonyl-L-phenylalanines (paragraph 6), the tissue-specific transporter function inhibitor according to paragraph 1, wherein the polymeric molecular structure incapable of passing through a membrane tissue is an .alpha.-cyclodextrin structure (paragraph 7), the tissue-specific transporter function inhibitor according to any one of paragraphs 1 to 7, wherein the ligand recognized by a tissue-specific transporter is an organic anionic substance, an organic cationic substance, or a peptidergic substance (paragraph 8), the tissue-specific transporter function inhibitor according to any one of paragraphs 1 to 8, wherein the tissue-specific transporter is a small intestine-specific transporter (paragraph 9), the tissue-specific transporter function inhibitor according to paragraph 9, wherein the small intestine-specific transporter is an oligopeptide transporter 1 (PEPT 1) (paragraph 10), and the tissue-specific transporter function inhibitor according to paragraph 10, wherein a peptidergic substance recognized by the oligopeptide transporter 1 (PEPT 1) is valyl-lysine (Val-Lys) (paragraph 11).

The present invention also relates to a therapeutic drug for tissue dysfunction diseases which contains the tissue-specific transporter function inhibitor according to any one of paragraphs 1 to 11 as an active ingredient (paragraph 12), and a therapeutic drug for suppressing the progress of chronic renal failure which contains the tissue-specific transporter function inhibitor according to any one of paragraphs 1 to 11 as an active ingredient, wherein the inhibitor is a protein absorption inhibitor (paragraph 13).

DETAILED DESCRIPTION OF THE INVENTION

As a tissue-specific transporter function inhibitor according to the present invention, any substance can be used as long as it has a ligand structure recognized by a tissue-specific transporter and a polymeric molecular structure incapable of passing through a membrane tissue, and inhibits the function of the above-mentioned tissue-specific transporter, however, those that have physiologically stable structures are preferable. Examples of the tissue include; small intestine, kidney, brain, liver, placenta, pancreas, lung, stomach, ovary, testis, spleen, large intestine, skeletal muscle, airway, bone marrow, prostate gland, heart, uterus, spinal cord, adrenal gland, thyroid gland, etc., and specific examples of the transporters which specifically express in such tissue include, but not limited to, transporters shown in Tables 1 to 3 (see Original Patent).

As the above-mentioned polymeric molecular structure incapable of passing through a membrane tissue, any structure can be used as long as it is a polymeric structure incapable of or having difficulty in passing through a membrane tissue in a living organism, for example, a membrane tissue in small intestine, kidney, brain, liver, placenta, pancreas, lung, stomach, ovary, testis, spleen, large intestine, skeletal muscle, airway, bone marrow, prostate gland, heart, uterus, spinal cord, adrenal gland, thyroid gland, etc. The specific examples include a supramolecular structure such as a polyrotaxane compound in which a number of circular molecules are penetrated by linear molecules, and both ends of the linear molecules are capped by bulky substituents, and a derivative or a clathrate structure containing .alpha.-cyclodextrin. The specific examples of the circular molecules mentioned above include but not particularly limited to molecules such as cyclodextrin, .alpha.-, .beta.-, or .gamma.-cyclodextrin, crown ether, and cyclofructan. As the linear molecules, molecules such as polyethyleneglycol, polypropylene glycol, or copolymer of polyethyleneglycol and polypropylene glycol, polyamino acid, polysaccharides, etc. are exemplified, however, polyethyleneglycol and the like, to which a bulky substituent can be introduced, is preferable. The bulky substituent is not particularly limited as long as it can prevent desorption of the circular molecules mentioned above, and the specific examples include but not particularly limited to an oligopeptide comprising a unit or units of any one of N-benzyloxycarbonyl-L-phenylalanine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, aspartic acid, glutamic acid, glycine, serine, threonine, tyrosine, cysteine, lysine, arginine, histidine, or derivatives thereof.

The specific examples of the ligand recognized by a tissue-specific transporter in the present invention include an organic anionic substance, an organic cationic substance, a peptidergic substance and a substance having an amino group. For example, the specific examples of the ligand recognized by an oligopeptide transporter 1 (PEPT 1), a transporter that specifically expresses in the small intestine, include but not limited to oligopeptides such as a dipeptide and a tripeptide, derivatives thereof whose constitutive amino acid residues are modified, .beta.-lactam antibiotics such as cefadroxil and ceftibuten, ACE inhibitors such as captopril, bestatin which is an anticancer drug, and valacyclovir which is an antiviral drug.

As a therapeutic drug for tissue dysfunction diseases provided by the present invention, a drug that contains the tissue-specific transporter function inhibitor as an active ingredient, and as a therapeutic drug for suppressing the progress of chronic renal failure provided by the present invention, a drug that contains the tissue-specific transporter function inhibitor that suppresses protein absorption as an active ingredient are exemplified respectively. It is preferable for the therapeutic drugs to have shapes capable of being administered orally, intravenously, intraperitoneally, intranasaly, intracutaneously, subcutaneously, intramuscularly, or in other such manners. It is possible to conveniently determine the effective amount of the drugs to be administered in consideration of the types and compositions of the drugs, its administration route, age and body weight of patients, etc., and it is preferable to administer the effective amount of the drugs one to a few times a day. Further, in the case of oral administration, the drugs are usually administered in a form of a drug prepared by mixing with carriers for formulation. As the carriers for drug formulation, substances which are conventionally used in the drug formulation field, and does not react with the tissue-specific transporter function inhibitor according to the present invention are used. The oral administration of the drugs can be conducted at each meal, or before each meal.

In addition, specific examples of dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, transdermal preparations, respiratory tonics, injectable solutions. These drugs are prepared according to conventional methods, and liquid drugs, in particular, can be prepared also in a form that can be dissolved or suspended in water or other suitable media before use. Tablets and granules may be coated by known methods. The injectable solutions are prepared by dissolving the peptide-modified polymers of the present invention into water, however, if necessary, instead of water, saline or glucose solution may be used for dissolution, and buffers or preservatives may be added. These drugs may contain other therapeutically valuable components.

It is also possible to blend the tissue-specific transporter function inhibitor of the present invention, as a food material for ameliorating the symptoms of tissue dysfunction diseases or chronic renal failure, into foods and to take such foods as functional foods. The examples of such foods are: bread and confectionery including baked goods such as puddings, cookies, bread, cakes, jellies, rice crackers, Japanese sweets such as "yokan" (a sweet jelly made from bean jam), frozen desserts, chewing gums; noodles such as wheat noodles and buck wheat noodles; fish paste products such as steamed fish paste, fish ham, fish sausages; various beverages such as yogurt, yogurt drinks, juice, milk, soy milk, alcoholic drinks, coffee, tea, green tea, oolong tea, isotonic drinks; seasonings such as miso, soy sauce, dressings, mayonnaise, sweeteners; various delicatessen such as tofu, devil's tongue, "tsukudani" (fish boiled on soy sauce), jiao-zi, croquettes, salad, etc.
 

Claim 1 of 4 Claims

1. A function-inhibitor of PEPT1 (oligopeptide transporter 1) consisting of a rotaxane compound in which a number of cyclodextrins are threaded by linear molecules, and both ends of the linear molecules are capped with bulky substituents, to which a dipeptide or tripeptide recognized by PEPT1 is bound, wherein the linear molecules are selected from the group consisting of polyethyleneglycol, polypropylene glycol, or copolymer of polyethyleneglycol and polypropylene glycol, polyamino acid, and polysaccharides, and the bulky substituents are selected from the group consisting of an oligopeptide comprising a unit or units of any one of N-benzyloxycarbonyl-L-phenylalanine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, aspartic acid, glutamic acid, glycine, serine, threonine, tyrosine, cysteine, lysine, arginine, histidine.

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