WO2003070235A1 - Compositions medicinales inhibant les tryptases - Google Patents

Compositions medicinales inhibant les tryptases Download PDF

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WO2003070235A1
WO2003070235A1 PCT/JP2003/001814 JP0301814W WO03070235A1 WO 2003070235 A1 WO2003070235 A1 WO 2003070235A1 JP 0301814 W JP0301814 W JP 0301814W WO 03070235 A1 WO03070235 A1 WO 03070235A1
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tryptase
pharmaceutical composition
disease
par
naphthyl
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PCT/JP2003/001814
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French (fr)
Japanese (ja)
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Ryozo Oishi
Yoshinori Itoh
Toshiaki Sendo
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Torii Pharmaceutical Co., Ltd.
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Priority to AU2003211540A priority Critical patent/AU2003211540A1/en
Publication of WO2003070235A1 publication Critical patent/WO2003070235A1/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
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    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • A61P7/10—Antioedematous agents; Diuretics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates to a pharmaceutical composition for inhibiting tryptase, comprising 6,1-amidino 2′-naphthyl 4-guanidinobenzoate or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, the present invention relates to a drug for inhibiting proteinase-activated receptor-2 (PAR-2) comprising a compound having a tryptase inhibitory activity or a pharmaceutically acceptable salt thereof as an active ingredient.
  • PAR-2 proteinase-activated receptor-2
  • the present invention relates to a synthetic material.
  • Tryptase is a tetrameric element of the serine proteinase family expressed by mast cells and was isolated and purified from human lung in 1984. Tryptase is released into the extracellular space together with pre-synthesized mediators such as histamine, chymase and proteoglycan when mast cells are activated (Schwartz Lewis Seldin, 1981; Caughey Lazarus, 1988). Human tryptase is specific among serine proteinases in that it is sufficiently catalytically active in plasma and in the extracellular space [Schwartz Bradford, 1986; Goldstein Leong, 1992].
  • tryptase increases the contractility of airway smooth muscle (Sekizawa , 1989), and is known to destroy its bronchodilator effect by inactivating vasoactive intestinal peptides (Tam Caughey, 1990; TamFranconi, 1990; Franconi, 1989). This suggested that tryptase was a virulence mediator of asthma.
  • Tryptase has also been reported to be inhibited by common inhibitors of trypsin-like proteinases, for example, diisopropynolefnorolophosphate, phenylmethylsulfonylfluoride and tosyl L-lysine chloromethylketone (SmithHougland Harvima Schechter, 1988), they are said to be unsuitable for use in vivo because of their high toxicity and poor stability, and even unsuitable for in vitro tests.
  • common inhibitors of trypsin-like proteinases for example, diisopropynolefnorolophosphate, phenylmethylsulfonylfluoride and tosyl L-lysine chloromethylketone
  • peptide-arginine aldehydes leupeptin and antinepine (Cromlish Seidah, 1987) and (Caughey, 1993), which are known to have a tryptase inhibitory effect, also have an inhibitory effect on tryptase. Weak and limited in usefulness.
  • Japanese Patent Publication No. 9-500532 describes a purified human tryptase inhibitor molecule which is a polypeptide, and a tryptase inhibitor obtained from an extract of leech.
  • tryptase The relationship between tryptase and various diseases is as described above, and the following is also known. For example, it has been reported that mast cells are involved in renal interstitial fibroids, and that the major protease, tryptase, is involved in fibroblast proliferation and promotion of extracellular matrix synthesis. (J Am Soc Nephrol 12: 1668-1676, 2001).
  • tryptase inhibitory drugs include systemic anaphylactic disease, aspirin-sensitive asthma, asthma, interstitial lung disease, allergic disease, atopic disease, skin blistering symptoms, gingivitis, psoriasis, pulmonary fibrosis, Arthritis, periodontal disease, blood clotting disorders, It is considered to be effective as a therapeutic agent for various diseases caused by tryptase, such as renal interstitial fibrosis, side effects of X-ray contrast agents, and hay fever.
  • Proteinase-activated receptor is a type of G-protein-coupled receptor. The receptor activity is exposed by the cleavage of the N-terminal extracellular peptide chain of the receptor molecule at a specific site by agonist proteinase. Activated by binding of the lig sequence to another site on the receptor molecule.
  • PAR-1 was cloned as a human platelet thrombin receptor, revealing its unique activation mechanism. Since then, PAR-2, PAR-3, and PAR-4 have been cloned to date.
  • PARs Of the four PARs, PAR_1, PAR-3, and PAR-4 are thrombin receptors, whereas PAR-2 is not activated by thrombin at all, and some proteinases such as trypsin and tryptase are endogenous. It is identified as a potential agonist enzyme candidate.
  • PAR-1 plays an important role in the activation of human platelets, is widely distributed in the nervous system, digestive system, respiratory system, vascular system and others, and is involved in the control of various functions. Also, PAR-2, like PAR-1, is widely distributed in living organisms and modifies various functions different from PAR-1.
  • PAR-1 stimulation of vascular endothelium and neutrophils enhances selectin expression in both cells.
  • the generation of thrombin following vascular rupture induces vasodilation and neutrophil accumulation through PAR-1 stimulation, and is closely related to the progression of the inflammatory response. I am giving.
  • Proliferation of cultured vascular endothelial cells and smooth muscle cells is enhanced by stimulation with PAR-1 and PAR-2. This suggests that PAR-2 receptor stimulation is involved in intimal proliferative hyperplasia.
  • Mast cell tryptase has been identified as a PAR-2 receptor-stimulating proteinase in addition to trypsin.
  • PAR-2 present in the respiratory epithelium transmits information via inositol phospholipid metabolism, modulating LPS in airway epithelial cells, and neutrophils in lung epithelial cells.
  • PAR-2 present in the sensory nervous system, is involved in the development of inflammatory pain, while it induces various physiological actions such as promoting adhesion of spheres, while gastric mucosa secretes mucus via the release of CGRP and tachykinins. It has been reported that it promotes and has a protective effect on gastric mucosa.
  • a wide variety of effects can be expected, including release of substance and substance P, onset of hyperalgesia by tryptase II PAR-2 agonist peptide, anti-edema action, and anti-asthmatic action (tracheal constriction by PAR-2 stimulation in the respiratory tract).
  • its application as an ointment as an antipruritic in the case of atopic dermatitis, and as an inhibitor for hyperesthesia such as neuralgia and postherpetic pain can be greatly expected.
  • the present invention relates to a pharmaceutical composition for inhibiting tryptase, comprising as an active ingredient 6′-amidino 2′-naphthinole 4-guanidinobenzoate represented by the following formula or a pharmaceutically acceptable salt thereof.
  • the salt is preferably a mesylate
  • the tryptase is preferably human tryptase.
  • the present invention provides a systemic anaphylaxis, aspirin-sensitive asthma, asthma, interstitial, which comprises 6, -amidino 2'-naphthyl 4-guanidinobenzoate or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention relates to a pharmaceutical composition for treating or preventing a disease selected from the group consisting of periodontal disease, blood coagulation disorder, renal interstitial fibrosis, increased vascular permeability or pulmonary edema as a side effect of an X-ray contrast agent, and hay fever. .
  • the salt is preferably a mesylate salt
  • a suitable disease is pain, pruritus, interstitial cystitis, irritable bowel syndrome, or vascular permeability enhancement or a side effect of an X-ray contrast agent. Pulmonary edema.
  • the present invention relates to a pharmaceutical composition for inhibiting proteinase-activated receptor-12, comprising a compound having a tryptase inhibitory activity or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the tryptase is human tryptase
  • the compound having a tryptase inhibitory activity or a pharmaceutically acceptable salt thereof is 6,1-amidino-2,1-naphthyl-4-guanidinobenzoate or a mesylate thereof. preferable.
  • FIG. 1 is a graph showing the inhibitory effect of nafamostat mesilate and gabexate mesylate on the activity of purified tryptase derived from human lung.
  • Figure 2 shows a device for measuring protein permeability in cultured vascular endothelial cells.
  • FIG. 3 is a graph showing the effect of tryptase and proteinase-activated receptor ⁇ (PAR-2) agonist peptide (SLIGKV) on enhancing protein permeability in cultured vascular endothelial cells.
  • FIG. 4 is a graph showing the inhibitory effect of nafamostat mesilate on the enhancement of protein permeability by tryptase in cultured vascular endothelial cells.
  • FIG. 5 is a graph showing the inhibitory effect of nafamostat mesilate and gabexate mesilate on the vascular permeability enhancing effect in rat lung by the eodo contrast agent ixoxagulate.
  • FIG. 6 is a graph showing the inhibitory effect of nafamostat mesilate on changes in rat arterial blood oxygen partial pressure, carbon dioxide partial pressure, and pH by the eodo contrast agent oxaxalic acid.
  • FIG. 7 is a graph showing the inhibition of nafamostat mesilate on rat pulmonary edema (increase in water content, increase in Na + content and decrease in KT content) by the eodo contrast agent ixoxagulate.
  • 6′-amid used as an active ingredient of the pharmaceutical composition for inhibiting tryptase of the present invention Zinoh 2'-naphthyl 4-guanidinobenzoate can be produced according to the method described in JP-B-61-10663.
  • As the active ingredient of the pharmaceutical composition for inhibiting PAR-2 of the present invention 6′-amidinol 2′-naphthyl 4-guanidinobenzoate is a typical example.
  • the active ingredient of the pharmaceutical composition for inhibiting tryptase, the pharmaceutical for inhibiting PAR-2, and the active ingredient of the composition of the present invention may be any of parenteral administration such as intravenous, intramuscular, intradermal, subcutaneous, and topical administration or oral administration. Administration can also be by the route.
  • the dose depends on the method of administration, the purpose of treatment or prevention, the age and weight of the patient, etc., but is preferably about 0.005 to about 10 Omg ZKg body weight.
  • the active ingredient When the active ingredient is to be administered by intravenous, intramuscular, intradermal, subcutaneous, or other administration routes, it is administered in the form of an injection.
  • a buffer such as a phosphate buffer for maintaining the pharmaceutical composition usually at a pH of about 3.5 to 7 may be added.
  • sodium chloride, mannitol or sorbitol for adjusting isotonicity may be added. They can be in lyophilized or dissolved form, in the latter case containing an antimicrobial preservative, for example 0.2-0.3% of 4-hydroxybenzoic acid methyl ester or ethyl ester in solution. It is preferable that
  • Dosage forms for topical administration of the active ingredient include aqueous solutions, lotions or jellies, oil solutions or suspensions, or oily or emulsion ointments.
  • the concentration of the active ingredient is from about 0.08 to about 1.5 mg, preferably 0.25 to 1.0 mg, in about 10 ml of solution or about 10 g of jelly.
  • Oily solutions or suspensions for topical administration include, for example, wetting agents (eg, aluminum stearate) and surfactants having a Z or HLB value (hydrophilic-lipophilic ratio) of less than 10 (eg, glycemic).
  • the oily ointment is obtained, for example, by suspending the impeached component of the present invention in a spreadable oily ointment base to which a surfactant having an HLB value of less than 10 is optionally added.
  • Emulsion ointment is obtained by pulverizing an aqueous solution of the active ingredient of the present invention in a soft spreadable oily ointment base to which a surfactant having an HLB value of less than 10 is optionally added.
  • a preservative may be included.
  • dosage forms include tablets, granules, granules, powders, capsules and the like. It may be in the form of an inhalant or a spray. These preparations can be manufactured by applying ordinary methods as they are. Particularly, a preparation for oral administration is suitable as a therapeutic agent for neuralgia and post-herpetic pain, an ointment is preferable as an antipruritic agent, and an inhalant is preferable as a therapeutic agent for asthma attack.
  • the inhibitory activity of 6,1-amidino-2,1-naphthyl 4-guanidinobenzoate against tryptase derived from human was determined to be t-butyloxycarbonyl-L-phenylalanyl-L-seryl-L-arginine-4-methylcoumaryl-7-amide (Boc -Phe_Ser_Arg_MCA) was evaluated as a substance by comparing it with the inhibitory effect of a known tryptase inhibitor “gabexate” (described as compound 1 in WO 97/037969).
  • guanidino fatty acid derivatives of the formula (I) guanidino benzoic acid derivatives of the formula (II), guanidino phenol derivatives of the formula (III), and guanidino phenol derivatives of the formula (III)
  • a tryptase inhibitor comprising one or more active ingredients selected from amidinophenol derivatives and the like has been described:
  • R1 is a hydrogen atom, a halogen atom, a nitro group, an alkyl group, an anoreoxy group, Represents a carboxy group or an alkoxyl group, and n represents an integer of 3 to 6.
  • R1 is a hydrogen atom, a halogen atom, a nitro group, an alkyl group, an anoreoxy group, Represents a carboxy group or an alkoxyl group, and n represents an integer of 3 to 6.
  • R 2 represents a phenyl group, a naphthyl group, a substituted phenyl group or a substituted naphthyl group
  • R 3 represents various substituents.
  • Toriputa over peptidase inhibitory activity of methanesulfonic acid salt of the compound 2 ⁇ Pi 3 are each 3 0 IC 5 0 value. 0 and 4. 3 3 n M a was the fact Symbol mounting Have been.
  • Compound 4 only the compound names are listed, and there is no experimental proof that Compound 4 has the same tryptase inhibitory activity as Compounds 2 and 3. Nor is there any rationale to support it.
  • compound 2 is included in Patent No. 100 269 (Japanese Patent Publication No. 54-41583), while compound 4 is included in Patent No. 1 332 894 Both are licensed as different patents on the grounds that they differ from each other in terms of their chemical structure.
  • the present inventors have been conducting research on the mechanism of the development of vascular permeability and pulmonary edema as side effects of various contrast media, and in the process, some drugs have suppressed the side effects.
  • the administration of 6'-amidino-2, 1-naphthyl 4-guanidinobenzoate (3-10 mg / kg, iv) increased pulmonary vascular permeability and pulmonary edema. was found to be completely suppressed.
  • tryptase directly stimulates PAR-2 in vascular endothelial cells to cause an increase in protein permeability, and to reduce the side effects such as edema caused by contrast agents by tryptase ZPAR-2.
  • the system was found to be involved.
  • 6'-amidino 2'-naphthyl 4-guanidinobenzoate is very potent at inhibiting tryptase and may be due to excessive tryptase Diseases, e.g., systemic anaphylaxis, aspirin-sensitive asthma, asthma, interstitial lung disease, interstitial cystitis, irritable bowel syndrome, allergic diseases, atopic diseases, cutaneous blistering symptoms, gingivitis , Psoriasis, pulmonary fibrosis, arthritis, periodontal disease, blood coagulation disorders, renal interstitial fibrosis, side effects of X-ray contrast agents, hay fever, etc. it is conceivable that.
  • tryptase Diseases e.g., systemic anaphylaxis, aspirin-sensitive asthma, asthma, interstitial lung disease, interstitial cystitis, irritable bowel syndrome, allergic diseases, atopic diseases, cutaneous blistering symptoms, gingivitis , Psorias
  • the inhibitory effect of nafamostat mesilate on the activity of purified tryptase from human lung was measured.
  • a known gabexate mesylate was used as a control.
  • Nafamostat mesilate was dissolved in Tris-HC1 buffer, tryptase (final concentration: InM) was added, and the mixture was allowed to stand at 37 ° C for 5 minutes.
  • Boc-Phe-Ser-Arg_MCA final concentration: 3.75 ⁇
  • the reaction was stopped by soaking for -60 seconds. After centrifuging the mixture (13000 rotations, 5 minutes), the fluorescence intensity of the degradation product was measured at an excitation wavelength of 370 nm and a fluorescence wavelength of 46 nm, and used as an index of enzyme activity.
  • FIG. 1 is a graph showing the inhibitory effect of nafamostat mesinoleate and gabexate mesilate on the activity of purified tryptase derived from human lung.
  • nafamostat mesilate significantly and concentration-dependently inhibits the activity of purified tryptase derived from human lung, and its IC0 value is 0.016. nM. Meanwhile, the IC 5 0 value of mesyl Sangabe Kisato used as a control was 1 94 nM. It can be seen that nafamostat mesilate exhibits a remarkable inhibitory activity of about 12,000 times that of the known gabexate mesylate.
  • vascular endothelial cells ⁇ -aortic endothelial cells
  • trypsin and Serine-Leucine- ⁇ -so ⁇ eucine-Glycine-Lysine-Valine (SLIGKV) proteins are prematurely killed as PAR12 agonists.
  • SIGKV Serine-Leucine- ⁇ -so ⁇ eucine-Glycine-Lysine-Valine
  • Fig. 2 The apparatus shown in Fig. 2 was used to measure protein permeability.
  • This device consists of a plastic plate outer container and an insert that can be fitted inside the plate.
  • the bottom of the insert is a planar polycarbonate membrane (? 3.0- ⁇ , area 1.0 cm 2 ). Is installed.
  • DMEM Eagle's Medium
  • Ab-EB pepsin albumin
  • the vascular endothelial cells cultured in the insert were washed well with Krebs-Ringer solution (pH 7.4) and immersed in the plate. Pre-fill the plate with 1.5 ml of Krebs-Ringer solution and place Krebs-in on the insert.
  • FIG. 3 is a graph showing the effect of tryptase and proteinase-activated receptor (PAR-2) agonist peptide (SLIGKV) on enhancing protein permeability in cultured vascular endothelial cells. In the graph, each value indicates the average value SE.
  • Example 2 It is apparent from Example 2 above that the presence of tryptase enhances protein permeability in cultured vascular endothelial cells.
  • an experiment was conducted on the inhibitory action of nafamostat mesilate according to the same method as in Example 2. Except that nafamostat mesinolate was added together with tryptase in the insert, the same method as in Example 2 was used, and the amount of tryptase added was adjusted so that the final concentration was 1 ⁇ .
  • Fig. 4 shows the results.
  • Fig. 4 is a graph showing the inhibitory effect of nafamostat mesilate on the enhancement of protein permeability by tryptase in cultured vascular endothelial cells. In the graph, each value represents the average value S. ⁇ . 7) According to this test, the effect of tryptase on protein permeability enhancement was inhibited by nafamostat mesilate in a concentration-dependent manner, and its IC 50 value was 0.029 ⁇ .
  • Rats were anesthetized by intraperitoneal administration of pentobarbital Na (5 Omg / kg), and oxoxagluate (Hexabrix 320, Tanabe Seiyaku) (4 g / kg) was administered.
  • pentobarbital Na 5 Omg / kg
  • oxoxagluate Hexabrix 320, Tanabe Seiyaku
  • the injection volume was 16 m 1 / kg and the injection rate was 1.5 ml / min.
  • the animals were sacrificed by exsanguination, and the pulmonary artery was perfused with physiological saline, and the lung tissue was excised and weighed. Evans blue leaked into the lung tissue was extracted with formamide (4 ml Zg tissue wet weight) and quantified by absorbance at 62 Onm.
  • the lung tissue was dried at 60 ° C for 24 hours, and then the dry weight was measured. Vessel permeability was expressed as the amount of Evans Blue leaked into the tissues per unit dry weight. Further, for the purpose of Ru examined ⁇ function, the partial pressure of oxygen in arterial blood (Pa0 2), partial pressure of carbon dioxide (pAC0 2) the ⁇ Pi pH, administration of the contrast agent 5, 10, 20, 40 and i one after 60 minutes Monitoring was performed from the femoral artery using STAT (i-STAT Cooperation, New Jersey, USA). Further, for the purpose of examining pulmonary edema, one hour after administration of the contrast agent, rat lungs were excised, and the lung tissue water content, Na T and water content were measured.
  • Pa0 2 partial pressure of oxygen in arterial blood
  • pAC0 2 partial pressure of carbon dioxide
  • STAT i-STAT Cooperation, New Jersey, USA
  • FIGS. Figure 5 is a graph showing the inhibitory effect of nafamostat mesilate and gabexate mesylate on the vascular permeability-enhancing effect in rat lung by the eodo contrast agent ixadaric acid, where each value represents the mean soil SE. (Numbers in parentheses; number of cases; * P ⁇ 0.05, ** P0.01; comparison with control group (Dunnett's test)). As shown in FIG.
  • the administration of the eodo contrast agent ixoxagnoleic acid significantly enhanced vascular permeability in rat lungs.
  • Nafamostat mesilate (3-10 mg / kg) significantly and potently suppressed the vasopermeability-increasing effect of ixoxagulic acid, and in particular, no vasoaugmentation enhancement by ixoxagulic acid was observed in the 10 mg / kg group.
  • gabexate mesylate 50 mg / kg significantly inhibited the vascular permeability-increasing effect of ixoxagulate, but not as markedly as nafamostat mesilate.
  • Fig. 6 is a graph showing the inhibitory effect of nafamostat mesilate on changes in rat arterial blood oxygen partial pressure, carbon dioxide partial pressure and pH by the eodo contrast agent oxaxalic acid. SE, using 4 to 6 rats in each group, * P ⁇ 0.05; comparison with non-administration group (Dunnett's test)), results shown in Figure 6 TJP03 / 01814
  • Fig. 7 is a graph showing the inhibitory effect of nafamostat mesylate on rat pulmonary edema (increased water content, increased Na + content, and decreased ⁇ ⁇ ⁇ ⁇ content) by the eodo-contrast agent oxaxuric acid (each value is the mean soil S.
  • Injections are prepared in the usual manner using the following ingredients.
  • the following components are dissolved in distilled water for injection and lyophilized to prepare an injection to be dissolved at the time of use.
  • the following components are dissolved in distilled water for injection and lyophilized to prepare an injection to be dissolved at the time of use.
  • the following components are dissolved in distilled water for injection and lyophilized to prepare an injection to be dissolved at the time of use.
  • the following components are mixed so that 100 mg of nafamostat mesilate is contained in one capsule, and a capsule is prepared by a conventional method.
  • Formulation The following ingredients and amounts are mixed so that 50 mg of nafamostat mesilate is contained in 50 mg of the preparation, and a fine granule is prepared by a usual method.
  • nafamostat mesilate is contained in 1 g of the cream, and a talium preparation is prepared by a conventional method.
  • Carboxyvinyl polymer (1% aqueous solution) 5.0 g
  • IC 0 value is 0.016 nM.
  • efficacy of nafamostat mesilate was over 1200 times higher than that of gabexate mesylate.
  • the pharmaceutical composition for tryptase inhibition of the present invention comprises systemic anaphylactic disease, aspirin-sensitive asthma, asthma, interstitial lung disease, interstitial cystitis, irritable bowel symptom group, allergic unigenic disease, atopic disease.
  • Diseases cutaneous bullous disease, hypersensitivity, pain, pruritus, gingivitis, edema, psoriasis, pulmonary fibrosis, arthritis, periodontal disease, blood clotting disorders, renal interstitial fibrosis, side effects of X-ray contrast agents
  • Research and development as therapeutic agents for the treatment or prevention of diseases selected from the group consisting of vascular hyperpermeability or pulmonary edema and hay fever are greatly expected.
  • tryptase selectively activates proteinase-active Eich type receptors (PAR-2), which are widely distributed in the body, including vascular endothelial cells, gastrointestinal tract, sensory nerves, bronchi, etc. Tryptase also increases protein permeability in cultured vascular endothelial cells, based on the known fact that it causes contraction of airway smooth muscle, pain through the release of tachycun from sensory nerves, hyperalgesia, pruritus, inflammation and edema.
  • PAR-2 proteinase-active Eich type receptors
  • PAR-2 agonist peptide showed a similar effect, as shown in the above study, indicating that nafamostat mesilate potently enhances the activity of tryptase to enhance protein permeability in cultured vascular endothelial cells. In addition, it became clear that the concentration was suppressed in a concentration-dependent manner.
  • pulmonary insufficiency and anaphylaxis uniform effects as side effects of the positive contrast agent are considered to be mainly due to the effects of mast cell-derived histamine and tryptase.
  • the eodo contrast agent caused significant pulmonary vascular permeability enhancement, which was almost completely suppressed by nafamostat mesilate.
  • gabexate mesilate significantly suppressed pulmonary vascular hyperpermeability, but its effect was incomplete.
  • nafamostat mesilate strongly inhibits tryptase activity, and as a result, it is thought that the tryptase / PAR-2 system is involved in the aforementioned diseases, in particular, hyperesthesia such as neuralgia and postherpetic pain, It is expected to be effective in the treatment and prevention of diseases such as pruritus, edema and asthma.
  • the pharmaceutical composition for inhibition and the pharmaceutical composition for inhibition according to the present invention comprise the following: Xie's disease, aspirin-sensitive asthma, asthma, interstitial lung disease, allergic disease, atopic disease, cutaneous bullous disease, hypersensitivity, pruritus, gingivitis, edema, psoriasis, pulmonary fibrosis, arthritis,
  • a therapeutic agent for treating or preventing a disease selected from the group consisting of periodontal disease, blood coagulation disorder, renal interstitial fibrosis, vascular hyperpermeability or pulmonary edema as a side effect of an X-ray contrast agent, and hay fever.

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PCT/JP2003/001814 2002-02-22 2003-02-19 Compositions medicinales inhibant les tryptases WO2003070235A1 (fr)

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Cited By (5)

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GB2445920A (en) * 2007-01-25 2008-07-30 Mucokinetica Ltd Amidino compounds for treatment of respiratory disease
EP2305639A2 (en) * 2005-04-14 2011-04-06 Novartis AG Organic compounds
CN106580961A (zh) * 2016-12-07 2017-04-26 郑州仁宏医药科技有限公司 一种用于治疗特发性肺纤维化的西药组合及其应用
WO2019157358A1 (en) * 2018-02-09 2019-08-15 Genentech, Inc. Therapeutic and diagnostic methods for mast cell-mediated inflammatory diseases
US20230190697A1 (en) * 2020-03-31 2023-06-22 Ensysce Biosciences, Inc. Methods for treating viral infections with nafamostat

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WO2005120491A1 (ja) * 2004-06-14 2005-12-22 Torii Pharmaceutical Co., Ltd. 炎症性腸疾患の治療薬又は予防薬
EP2119440A1 (en) * 2005-05-17 2009-11-18 Santen Pharmaceutical Co., Ltd. Amidino derivatives for use in the prevention or treatment of retinitis pigmentosa and Leber's disease
JP2007186457A (ja) * 2006-01-13 2007-07-26 Ichimaru Pharcos Co Ltd トリプターゼ活性阻害剤およびその利用

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JPS611063B2 (enrdf_load_stackoverflow) * 1980-09-16 1986-01-13 Torii Yakuhin Kk
WO1997037969A1 (fr) * 1996-04-10 1997-10-16 Ono Pharmaceutical Co., Ltd. Inhibiteur de tryptase derives de guanidino

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JPS611063B2 (enrdf_load_stackoverflow) * 1980-09-16 1986-01-13 Torii Yakuhin Kk
WO1997037969A1 (fr) * 1996-04-10 1997-10-16 Ono Pharmaceutical Co., Ltd. Inhibiteur de tryptase derives de guanidino

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2305639A2 (en) * 2005-04-14 2011-04-06 Novartis AG Organic compounds
GB2445920A (en) * 2007-01-25 2008-07-30 Mucokinetica Ltd Amidino compounds for treatment of respiratory disease
WO2008090366A1 (en) * 2007-01-25 2008-07-31 Mucokinetica Ltd. Treatment for respiratory disease
CN106580961A (zh) * 2016-12-07 2017-04-26 郑州仁宏医药科技有限公司 一种用于治疗特发性肺纤维化的西药组合及其应用
WO2019157358A1 (en) * 2018-02-09 2019-08-15 Genentech, Inc. Therapeutic and diagnostic methods for mast cell-mediated inflammatory diseases
CN111787947A (zh) * 2018-02-09 2020-10-16 豪夫迈·罗氏有限公司 用于肥大细胞介导的炎性疾病的治疗和诊断方法
US20230190697A1 (en) * 2020-03-31 2023-06-22 Ensysce Biosciences, Inc. Methods for treating viral infections with nafamostat

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