WO2012063487A1 - アラレマイシン又はその誘導体を有効成分とする抗マラリア薬 - Google Patents
アラレマイシン又はその誘導体を有効成分とする抗マラリア薬 Download PDFInfo
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- WO2012063487A1 WO2012063487A1 PCT/JP2011/006273 JP2011006273W WO2012063487A1 WO 2012063487 A1 WO2012063487 A1 WO 2012063487A1 JP 2011006273 W JP2011006273 W JP 2011006273W WO 2012063487 A1 WO2012063487 A1 WO 2012063487A1
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- malaria
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- araremycin
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- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000004992 toluidines Chemical class 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229940035936 ubiquinone Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
-
- 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
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
-
- 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 antimalarial drug useful for the prevention and / or treatment of infectious diseases caused by malaria parasites. More specifically, the present invention relates to 5-acetamido-4-oxo-5-hexenoic acid (araremycin) or a derivative thereof as an active ingredient. The present invention relates to a preventive and / or therapeutic agent for malaria contained as
- Malaria is an infectious disease caused by malaria parasites transmitted by anopheles, and has been the most feared infectious disease of civilization since history, mainly in the tropical and subtropical regions. Due to specific drugs such as quinine and chloroquine, the number of infected people decreased for a while, but drug-resistant protozoa began to be discovered in the late 1950s, and 300 to 500 million people are infected as revitalizing infections annually. The death toll is said to be 1 million or 2 million. Many other infectious diseases have been treated and prevented with vaccines.For example, smallpox has been completely eradicated, but in the case of malaria, infection is caused by protozoa and has a complicated life cycle. Despite research being conducted, even the clue of vaccine development has not been found, and it is said that vaccine development is inherently difficult.
- Aralemycin is a porphobilinogen synthase (Porphobilinogen synthase) that is a porphyrin-heme biosynthetic enzyme that synthesizes porphobilinogen (PBG) using 5-aminolevulinic acid (5-ALA) as a substrate. It was proved that it acts as an inhibitor of Synthase (PBGS) (Non-patent Document 3).
- PBGS is classified into two types based on the difference in metal ions that are cofactors. One is a Zn 2+ type distributed in animal cells including humans and many bacteria, and the other is one such as plant cells and Pseudomonas aeruginosa. Mg 2+ type distributed in some bacteria (Non-Patent Documents 4, 5, and 6).
- PBGS is involved in the synthesis of porphyrins and related compounds that are indispensable for the survival of living organisms, and its inhibitor, araremycin, is an opportunistic infection not only in Escherichia coli used for screening of producing bacteria but also in hospitals. It also has antibacterial activity against Pseudomonas aeruginosa, which is a problem as a resistant bacterium (Non-patent Document 3). Since PBGS of Pseudomonas aeruginosa is an Mg 2+ type PBGS that differs in structure from that of humans, it is considered that Mg 2+ type PBGS can be an effective target molecule in terms of antibacterial agents.
- the acid amide compound of araremycin represented by the following formula (B) is known as an anticancer antibiotic primocarcin (Non-patent Document 7).
- a methyl ester compound of araremycin represented by the following formula (C) is known as a photosensitizer for cancer photodynamic therapy (Patent Document 1).
- Non-patent Document 7 it is known that malaria parasites have Mg2 + type PBGS and synthesize new heme even though they live by ingesting a large amount of hemoglobin (Non-patent Documents 8 and 9).
- Atovaquone an antimalarial agent already put into practical use as a pharmaceutical, specifically inhibits the cytochrome bc1 complex (complex III) present in the mitochondrial membrane of human malaria parasite (non-patented). Reference 10). This suggests that the mitochondrial electron transport system is essential for protozoan growth.
- Non-patent Document 11 it is known that malaria parasites cannot use host-derived pyrimidines (Non-patent Document 12).
- An object of the present invention is to provide an antimalarial drug useful for the prevention and / or treatment of malaria containing 5-acetamido-4-oxo-5-hexenoic acid (araremycin) or a derivative thereof as an active ingredient, and prevention using the same And / or providing a therapeutic method.
- araremycin 5-acetamido-4-oxo-5-hexenoic acid
- the present inventors closely tracked the mechanism of action of antimalarial drugs typified by quinine, chloroquine, and atobacon, and studies on resistance to these antimalarial drugs.
- aralemycin inhibits PBGS, cytochrome C, etc.
- the idea was that a series of heme protein functions would be lost, the mitochondrial electron transport system would fail, the pyrimidine synthesis system would not work, nucleic acid synthesis and protein synthesis would be significantly inhibited, and the growth of malaria parasites could be suppressed. If the growth of plasmodium parasites in erythrocytes is suppressed, plasmodium turnover will eventually result in the disappearance of plasmodium.
- the present invention (1) Formula (I) (Wherein R 1 represents a hydroxy group, an amino group, a substituted or unsubstituted linear or branched alkoxy group having 1 to 8 carbon atoms or an alkylamino group, and R 2 represents hydrogen, substituted or unsubstituted, A linear or branched alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted aromatic group having 4 to 10 carbon atoms, and R 3 represents hydrogen or a methyl group.
- the present invention relates to a preventive and / or therapeutic agent for malaria, which contains, as an active ingredient, araremycin or a derivative thereof or a pharmacologically acceptable salt thereof.
- the present invention also provides: (2) R 1 is hydroxy group, R 2 is a methyl group, the prevention and / or or therapeutic agent for malaria above (1) wherein the R 3 is hydrogen, (3) R 1 is a methoxy group, R 2 is a methyl group, and R 3 is hydrogen, and the preventive and / or therapeutic agent for malaria according to the above (1), and (4) R 1 is an amino group , R 2 is a methyl group, and R 3 is hydrogen.
- the present invention relates to the preventive and / or therapeutic agent for malaria according to (1) above.
- the present invention provides compounds of formula (I) (Wherein R 1 represents a hydroxy group, an amino group, a substituted or unsubstituted linear or branched alkoxy group having 1 to 8 carbon atoms or an alkylamino group, and R 2 represents hydrogen, substituted or unsubstituted, A linear or branched alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted aromatic group having 4 to 10 carbon atoms, and R 3 represents hydrogen or a methyl group.
- a method for preventing and / or treating malaria comprising the step of administering to a patient in need thereof a drug containing, as an active ingredient, araremycin or a derivative thereof or a pharmacologically acceptable salt thereof And a method of using alaremycin represented by formula (I) or a derivative thereof or a pharmacologically acceptable salt thereof for the prevention and / or treatment of malaria.
- the araremycin or a derivative thereof of the present invention is useful as an agent for treating and / or preventing malaria.
- the alkoxy group having 1 to 8 carbon atoms and the alkyl moiety of the alkylamino group and the alkyl group having 1 to 8 carbon atoms may be any of linear or branched alkyl groups. Examples include groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl and the like. Further, any of substituted or unsubstituted alkyl groups may be used.
- substituents include 1) halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; 2) methoxy, ethoxy, And alkoxy groups such as propoxy and isopropoxy; 3) substituted or unsubstituted cyclic alkyl groups having 4 to 6 carbon atoms; 4) substituted or unsubstituted aromatic groups having 4 to 10 carbon atoms.
- the cyclic alkyl group and the aromatic group may contain one or more elements of oxygen, sulfur, and nitrogen, and may be composed of two or more kinds of elements.
- cyclic alkyl group having 4 to 6 carbon atoms include cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholyl, piperidyl, tetrahydropyranyl and the like.
- aromatic group having 4 to 10 carbon atoms include pyrrolyl, imidazoyl, oxazoyl, pyrazyl, pyrimidyl, furanyl, thiophenyl, pyridyl, phenyl, indoyl, benzoxazoyl, quinolyl, isoquinolyl, chromenyl, naphthalenyl, and the like. Each group is mentioned.
- fluorine atom chlorine atom, hydroxy group, amino group, cyano group, nitro group, trifluoromethyl group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group And isopropoxy group.
- the aromatic group having 4 to 10 carbon atoms in the compound (I) may be either a substituted or unsubstituted aromatic group.
- fluorine atom chlorine atom, hydroxy group, amino group, cyano group, nitro group, trifluoromethyl group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group And isopropoxy group.
- pharmacologically acceptable metal salts examples include alkali metal salts such as lithium, sodium and potassium, alkaline earth metal salts such as magnesium and calcium, and metal salts such as aluminum and zinc.
- pharmacologically acceptable metal salts include alkali metal salts such as lithium, sodium and potassium, alkaline earth metal salts such as magnesium and calcium, and metal salts such as aluminum and zinc.
- the physically acceptable ammonium salt include ammonium and tetramethylammonium salts
- examples of the pharmacologically acceptable organic amine salt include triethylamine, piperidine, morpholine, toluidine and the like.
- the compounds represented by the formula (I) for example, the compounds represented by the formulas (A) to (C) described above are known compounds, and the compounds in which R 1 is an alkoxy group are derived from the compound (A): It can be obtained by esterification by a conventional method.
- the compound (I) can be purified as it is when it is obtained in the form of a salt. What is necessary is just to make it melt
- the compound represented by formula (I) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts can also be used in the present invention. it can.
- the compound represented by formula (I) used as the antimalarial drug of the present invention is not particularly limited as long as it is compound (I), but R 2 is a methyl group, R 3 is hydrogen, and R 1 is hydroxy group (Arale clarithromycin), methoxy group, an ethoxy group, a compound which is either an amino group (Purimokarushin) are more preferred, compounds where R 1 is hydroxy group are particularly preferred.
- the compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to prepare various pharmaceutical preparations. It can be produced by a conventional method of pharmaceutics by mixing with one or two or more types of carriers that are acceptable.
- Administration routes include parenteral administration such as oral administration, inhalation administration, and intravenous administration.
- Examples of the dosage form include tablets, injections, etc.
- the tablets are mixed with various additives such as lactose, starch, magnesium stearate, hydroxypropyl cellulose, polyvinyl alcohol, surfactant, glycerin, etc.
- the inhalant may be produced according to a conventional method by adding, for example, lactose.
- An injection may be produced according to a conventional method by adding water, physiological saline, vegetable oil, solubilizer, preservative and the like.
- the effective amount and frequency of administration of compound (I) or a pharmacologically acceptable salt thereof vary depending on the administration form, patient age, body weight, symptoms, etc., but usually 0.001 mg to 5 g per adult, preferably Is administered in an amount of 0.1 mg to 1 g, more preferably 1 to 500 mg, once to several times a day.
- Human erythrocytes infected at 2% infection rate with human malaria parasite in the ring phase were cultured in RPMI 1640 medium (Invitrogen) containing AlbuMAX-II at 37 ° C. with hematocrit 4%. 50 ⁇ L of the culture solution was mixed with 50 ⁇ L of a medium containing aralemycin to obtain the respective concentrations shown in Table 1, and [ 3 H] -hypoxanthine and [ 14 C] -isoleucine were added, and cultured at 37 ° C. in a 96-well plate. did. The number of replicates was 2 for each concentration.
- nucleic acid metabolism and protein synthesis of human malaria parasites were inhibited by araremycin in a concentration-dependent manner. Nucleic acid metabolism and protein synthesis were inhibited to approximately the same extent by the same concentration of araremycin. In general, radioactivity uptake was inhibited by approximately 50% by araremycin at a concentration of 15 ⁇ M, and by 95% or more by araremycin at a concentration of 50 ⁇ M.
- R 1 is a methoxy group
- R 1 is an ethoxy group
- the inhibition of nucleic acid metabolism and protein synthesis of human malaria parasites was measured according to araremycin. It was confirmed that nucleic acid metabolism and protein synthesis were inhibited to the same extent by a compound that was a group and a compound that was an ethoxy group, but inhibition by araremycin was found to be superior to these compounds.
- Human erythrocytes infected at 2% infection rate with human malaria parasite in the ring phase were cultured at 37 ° C. with hematocrit 4% in RPMI 1640 medium containing AlbuMAX-II.
- 50 ⁇ L of a medium containing araremycin or other compounds shown in Table 2 and 50 ⁇ L of the culture solution were mixed to obtain various concentrations, [ 3 H] -hypoxanthine was added, and the cells were cultured at 37 ° C. in a 96-well plate. The number of replicates was 2 for each concentration.
- araremycin is significantly less concentrated than the compounds with similar skeleton succinylacetone (SA: 4,6-dioxoheptanoic acid) and 4,7-dioxosebacic acid (DOSA). It was found to sufficiently inhibit the nucleic acid metabolism of human malaria parasites.
- SA 4,6-dioxoheptanoic acid
- DOSA 4,7-dioxosebacic acid
- Tablets are prepared by a conventional method using a composition comprising 10 mg of aralemycin, 70 mg of lactose, 15 mg of starch, 4 mg of polyvinyl alcohol and 1 mg of magnesium stearate (total 100 mg).
- the antimalarial drug containing araremycin or a derivative thereof of the present invention as an active ingredient can be used as a therapeutic and / or prophylactic agent for malaria.
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Abstract
Description
(1)式(I)
で表わされるアラレマイシン(Alaremycin)若しくはその誘導体又はその薬理学的に許容される塩を有効成分として含有するマラリアの予防及び/又は治療剤に関する。
また、本発明は、
(2)R1がヒドロキシ基、R2がメチル基、R3が水素であることを特徴とする上記(1)記載のマラリアの予防及び/又は治療剤や、
(3)R1がメトキシ基、R2がメチル基、R3が水素であることを特徴とする上記(1)記載のマラリアの予防及び/又は治療剤、及び
(4)R1がアミノ基、R2がメチル基、R3が水素であることを特徴とする上記(1)記載のマラリアの予防及び/又は治療剤に関する。
別の態様として、本発明は、式(I)
で表わされるアラレマイシン(Alaremycin)若しくはその誘導体又はその薬理学的に許容される塩を有効成分として含有する医薬を、それを必要とする患者に投与する工程を含むマラリアの予防及び/又は治療方法や、式(I)で表わされるアラレマイシン(Alaremycin)若しくはその誘導体又はその薬理学的に許容される塩をマラリアの予防及び/又は治療に使用する方法に関する。
Claims (4)
- R1がヒドロキシ基、R2がメチル基、R3が水素であることを特徴とする請求項1記載のマラリアの予防及び/又は治療剤。
- R1がメトキシ基、R2がメチル基、R3が水素であることを特徴とする請求項1記載のマラリアの予防及び/又は治療剤。
- R1がアミノ基、R2がメチル基、R3が水素であることを特徴とする請求項1記載のマラリアの予防及び/又は治療剤。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/883,038 US9295660B2 (en) | 2010-11-10 | 2011-11-09 | Antimalarial drug comprising alaremycin or derivative thereof as active ingredient |
EP11840434.2A EP2638902B1 (en) | 2010-11-10 | 2011-11-09 | Antimalarial drug comprising alaremycin or derivative thereof as active ingredient |
JP2012542816A JP5669111B2 (ja) | 2010-11-10 | 2011-11-09 | アラレマイシン又はその誘導体を有効成分とする抗マラリア薬 |
HK13113695.6A HK1186655A1 (zh) | 2010-11-10 | 2013-12-10 | 含有 或其衍生物用作活性成分的抗瘧疾藥物 |
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JP2010251562 | 2010-11-10 |
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US (1) | US9295660B2 (ja) |
EP (1) | EP2638902B1 (ja) |
JP (1) | JP5669111B2 (ja) |
HK (1) | HK1186655A1 (ja) |
WO (1) | WO2012063487A1 (ja) |
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- 2011-11-09 US US13/883,038 patent/US9295660B2/en not_active Expired - Fee Related
- 2011-11-09 WO PCT/JP2011/006273 patent/WO2012063487A1/ja active Application Filing
- 2011-11-09 EP EP11840434.2A patent/EP2638902B1/en active Active
- 2011-11-09 JP JP2012542816A patent/JP5669111B2/ja active Active
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JP2006282577A (ja) | 2005-03-31 | 2006-10-19 | Rikogaku Shinkokai | ガン光線力学治療用新規光増感剤 |
Non-Patent Citations (16)
Title |
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ANTIMICROB.AGENTS CHEMOTHER, vol. 54, 2010, pages 267 - 272 |
BIOCHEM.BIOPHYS.RES.COMM., vol. 187, 1992, pages 744 - 750 |
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BIOSCI.BIOTECHNOL.BIOCHEM., vol. 69, 2005, pages 1721 - 1725 |
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HEINEMANN I.U. ET AL.: "Structure of the Heme Biosynthetic Pseudomonas aeruginosa Porphobilinogen Synthase in Complex with the Antibiotic Alaremycin", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 54, no. 1, January 2010 (2010-01-01), pages 267 - 272, XP055084736 * |
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KERVINEN J ET AL.: "Mechanistic Basis for Suicide Inactivation of Porphobilinogen Synthase by 4,7-Dioxosebacic Acid, an Inhibitor That Shows Dramatic Species Selectivity", BIOCHEMISTRY, vol. 40, no. 28, 17 July 2001 (2001-07-17), pages 8227 - 8236, XP002991518 * |
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See also references of EP2638902A4 |
SUROLIA N ET AL.: "De novo biosynthesis of heme offers a new chemotherapeutic target in the human malarial parasite", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 187, no. 2, 16 September 1992 (1992-09-16), pages 744 - 750, XP024836990 * |
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US20130217913A1 (en) | 2013-08-22 |
EP2638902B1 (en) | 2016-02-24 |
JP5669111B2 (ja) | 2015-02-12 |
US9295660B2 (en) | 2016-03-29 |
JPWO2012063487A1 (ja) | 2014-05-12 |
HK1186655A1 (zh) | 2014-03-21 |
EP2638902A1 (en) | 2013-09-18 |
EP2638902A4 (en) | 2014-04-16 |
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