WO2001052891A1 - Inhibiteurs d'invasion plasmodiale dans des erythrocytes - Google Patents

Inhibiteurs d'invasion plasmodiale dans des erythrocytes Download PDF

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Publication number
WO2001052891A1
WO2001052891A1 PCT/JP2001/000336 JP0100336W WO0152891A1 WO 2001052891 A1 WO2001052891 A1 WO 2001052891A1 JP 0100336 W JP0100336 W JP 0100336W WO 0152891 A1 WO0152891 A1 WO 0152891A1
Authority
WO
WIPO (PCT)
Prior art keywords
malaria
invasion
erythrocytes
plasmodium
compound
Prior art date
Application number
PCT/JP2001/000336
Other languages
English (en)
Japanese (ja)
Inventor
Satoru Kawai
Jun Matsumoto
Hajime Matsuda
Keiji Terao
Kosuke Haruki
Kohichiro Yoshino
Original Assignee
Nippon Organon K. K.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nippon Organon K. K. filed Critical Nippon Organon K. K.
Publication of WO2001052891A1 publication Critical patent/WO2001052891A1/fr

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Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to an agent for inhibiting erythrocyte invasion of Plasmodium malaria, which comprises, as an active ingredient, a metal enzyme, particularly a compound having an activity of inhibiting the enzyme activity of a metal enzyme whose metal is zinc.
  • Malaria is a disease caused by the transmission of Plasmodium malaria (P1 asmodium) transmitted by Anopheles mosquitoes.
  • P1 asmodium Plasmodium malaria
  • Anopheles mosquitoes Currently, 300 to 500 million people worldwide, mainly in tropical and subtropical countries. Are infected with malaria, of which it is estimated that 150 to 2.7 million people have died.
  • Malaria includes Plasmodium falciparum, Plasmodium falciparum, Plasmodium vivax, P1 asmodiumvivax, and Quarter falciparum Plasmodium 'P.
  • malaria (Plasmodiumma 1 ariae)' and Oval-shaped Plasmodium 'plasmadium' (PI asmodiumova 1e) are caused by infection, but the symptoms depend on the type of protozoan.
  • malaria which has a fatal outcome from severe malaria, is Plasmodium falciparum, a falciparum malaria caused by falciparum, and the morbidity is also high. Most.
  • anti-malarial drugs such as cloquine are mainly used to treat malaria. Although it is used, malaria has the same problems as bacterial drug resistance, such as the emergence of cloroquine-resistant strains with the spread of ku mouth-to-kin treatment. However, effective antimalarial drugs are becoming scarce and making treatment difficult. Disclosure of the invention
  • An object of the present invention is to provide a red blood cell invasion inhibitor of malaria parasite, which is used as a preventive and therapeutic agent for the development of malaria, particularly falciparum malaria.
  • the present inventors have found that in the post-infection process, malaria parasites enter the erythrocytes and proliferate violently (intra-erythrocytic multiple division), resulting in a dozen or so daughter daughters ( The merozoites destroy the red blood cells (in this case, a fever attack occurs and malaria develops), and the newly born merozoites invade and multiply into more red blood cells If we were able to prevent these processes from invading erythrocytes, we would be able to prevent malaria from developing, and we would be able to prevent malaria from developing. Thought that it would lead to the treatment of Malaria.
  • the present inventors have found that a compound having an inhibitory effect on the enzymatic activity of a metalloenzyme, particularly a metalloenzyme whose metal is zinc, can suppress the entry of Malaria parasite into erythrocytes.
  • the present inventors have found that the present invention has been shown, and confirmed that this effect prevents the onset of malaria, thereby completing the present invention.
  • a compound having an inhibitory effect on the enzyme activity of a metalloenzyme particularly a metalloenzyme whose metal is zinc is used.
  • These compounds are not particularly limited as long as they can suppress the process by which the malaria parasite enters the erythrocytes based on the action.
  • the compound suitably used in the present invention has an enzyme activity of a metalloenzyme.
  • a predetermined amount of the compound having inhibitory activity is added to a culture solution obtained by appropriately infecting (parasitizing) erythrocytes with malaria parasites for a predetermined time (4 8-7 2 hours) It can be easily selected by culturing and measuring the rate of post-culture cultivation.
  • the compound used in the present invention include, for example, [4— (N—hydroxyamino) -12 (R) -1-isobutyl-13 (S) —methylsuccinyl] — L-phenylidyne-N-hydroxamic acid derivatives such as methylamide.
  • the above hydroxamic acid derivative can be produced by the production method described in International Publication WO95 / 047515.
  • hydroxamic acid derivative suitably used in the present invention, N- [2,2—dimethyl-1- (S)-(N—methylcarnox umino) propyl] —N, 3 (S) — Dihydroxy 2 (R) — Isobutyl succinamide (generic name; marimastat).
  • the marimasut can be produced by the production method described in the British Published Patent Application (GB2266934A).
  • the malaria parasite red blood cell invasion inhibitor of the present invention may be used for malaria patients or those who may be infected with malaria (inhabitants, residents and malaria-endemic areas of malaria-endemic areas). It can be administered to tourists, etc.) in the form of oral preparations or injections.
  • Dosage forms for oral administration include tablets, capsules, granules, fine granules, powders, and the like. These preparations contain the compound used in the present invention, lactose, and costar. Mix, cellulose cellulose, magnesium stearate, magnesium oleoresinol canolexenolose, oleoresinol, hydroxypropinolesenol, and other ordinary pharmaceutical additives such as talc, talc, etc. Manufactured.
  • Injectables can be manufactured by a conventional method, and if necessary, mannitol Isotonicity agents such as sodium chloride, glucose, sonorebit, grease mouth, xylitol, fructos, maltose, mannose, etc., sulfite Stabilizers such as sodium and albumin, benzyl alcohol, phenol, etc. Preservatives such as methyl hydroxybenzoate can be added to the preparation.
  • mannitol Isotonicity agents such as sodium chloride, glucose, sonorebit, grease mouth, xylitol, fructos, maltose, mannose, etc.
  • sulfite Stabilizers such as sodium and albumin, benzyl alcohol, phenol, etc.
  • Preservatives such as methyl hydroxybenzoate can be added to the preparation.
  • Injectables can also be lyophilized preparations for dissolution before use.
  • the freeze-dried preparation can be produced by a conventional method, and the above-mentioned isotonic agent, stabilizer, preservative, and the like can be appropriately added to the preparation.
  • the dose of the malaria parasite erythrocyte invasion inhibitor of the present invention depends on the compound used in the present invention, the administration route, the type of malaria parasite infected and the condition, age, weight, etc. of the patient. However, depending on whether it is used therapeutically or prophylactically, it is usually between 0.1 mg and 100 mg per day, which can be taken at once or twice a day. Administer the drug as needed, dividing it into three times.
  • the malaria parasite erythrocyte invasion inhibitor of the present invention includes antimalarial agents such as black mouth quinine, quinine, mefloquine and the like, and no or primaquine, pamaquine, pyrimethamine. A more effective preventive and / or therapeutic effect can be expected when used in combination with a recurrence preventive drug.
  • the protozoan growth inhibition rate (IC5Q value) was calculated using the amount of hypoxanthine uptake in the culture solution coexisting with Plasmodium 'Falciparum as an index.
  • IC 5 o values force of the positive control click throat Kin ⁇ 1 8 5.
  • To 3 was a ⁇ 2 2.
  • 9 7 n M IC 50 values of the compounds A is Ri der least ⁇ ⁇ , The yidani compound has the power to substantially suppress the growth of plasmodial falciparum.
  • Predetermined concentration ( ⁇ ⁇ 1 ⁇ ⁇ , 500 ⁇ ⁇ , 200 ⁇ ⁇ , 100 ⁇
  • the agent for inhibiting erythrocyte invasion of Plasmodium malaria of the present invention includes a process by which a plasmodium of Malaria invades and proliferates into erythrocytes in a post-infection process, and the resulting merozoite is a erythrocyte. It has the effect of preventing and treating the onset of malaria by suppressing the process of invading and multiplying inside.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des inhibiteurs de l'invasion de plasmodes dans des érythrocytes contenant en tant qu'ingrédient actif des composés ayant un effet inhibiteur sur les enzymes contenant du métal (en particulier les enzymes contenant du zinc). Ces inhibiteurs inhibent le processus d'invasion dans les érythrocytes et la prolifération de plasmodes dans ceux-ci après l'infection, et le processus de l'invasion dans les érythrocytes et la prolifération des mérozoïtes ainsi formés dans ceux-ci, obtenant ainsi des effets préventifs et thérapeutiques sur le début du paludisme.
PCT/JP2001/000336 2000-01-20 2001-01-19 Inhibiteurs d'invasion plasmodiale dans des erythrocytes WO2001052891A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-48304 2000-01-20
JP2000048304 2000-01-20

Publications (1)

Publication Number Publication Date
WO2001052891A1 true WO2001052891A1 (fr) 2001-07-26

Family

ID=18570411

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/000336 WO2001052891A1 (fr) 2000-01-20 2001-01-19 Inhibiteurs d'invasion plasmodiale dans des erythrocytes

Country Status (1)

Country Link
WO (1) WO2001052891A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997043436A1 (fr) * 1996-05-14 1997-11-20 Pharmacia & Upjohn Ab Procede pour produire un polypeptide recombine comprenant l'addition d'un inhibiteur de proteases metal-dependantes ou de chymotrypsines au milieu de culture cellulaire
EP0712838B1 (fr) * 1993-08-09 1998-11-04 Kanebo Ltd. Derive d'acylphenylglycine et agent preventif et curatif, concernant des maladies causees par une activite collagenase accrue, contenant un tel compose comme ingredient actif

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0712838B1 (fr) * 1993-08-09 1998-11-04 Kanebo Ltd. Derive d'acylphenylglycine et agent preventif et curatif, concernant des maladies causees par une activite collagenase accrue, contenant un tel compose comme ingredient actif
WO1997043436A1 (fr) * 1996-05-14 1997-11-20 Pharmacia & Upjohn Ab Procede pour produire un polypeptide recombine comprenant l'addition d'un inhibiteur de proteases metal-dependantes ou de chymotrypsines au milieu de culture cellulaire

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
A.R.DLUZEWSKI et al. "Plasmodium falciparum: Protease Inhibitors and Inhibition of Erythrocyte Invasion", Experimental Parasitology, 1986, Vol. 62, pp.416-422 *

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