WO2001080809A2 - Medicament for the treatment of diseases caused by parasitic protozoa - Google Patents
Medicament for the treatment of diseases caused by parasitic protozoa Download PDFInfo
- Publication number
- WO2001080809A2 WO2001080809A2 PCT/SE2001/000864 SE0100864W WO0180809A2 WO 2001080809 A2 WO2001080809 A2 WO 2001080809A2 SE 0100864 W SE0100864 W SE 0100864W WO 0180809 A2 WO0180809 A2 WO 0180809A2
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- WO
- WIPO (PCT)
- Prior art keywords
- ctp
- don
- pharmaceutical composition
- disease
- trypanosomiasis
- Prior art date
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- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 description 1
- 235000020925 non fasting Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000037360 nucleotide metabolism Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000885 phytotoxic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 244000062645 predators Species 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 230000006825 purine synthesis Effects 0.000 description 1
- 230000004147 pyrimidine metabolism Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000007058 regulation of lipid biosynthetic process Effects 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000002305 strong-anion-exchange chromatography Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 125000002264 triphosphate group Chemical group [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- 230000000654 trypanocidal effect Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 239000008215 water for injection Substances 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
- A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- 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
-
- 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
- African sleeping sickness (for a review see Brun, R. (1999) Karger-Gazette 63, 5-7) is a devastating disease that has got its name from the comatose condition at the final stage of the disease. Without treatment, the patient dies within a couple of months to several years after infection. The severe comatose condition described occurs when these parasites from mainly being circulating in the bloodstream also invade the central nervous system.
- T. brucei is spread between its mammalian hosts by tsetse flies.
- the parasite goes through many different life cycle stages in the mammalian host as well as in the fly (Vickerman, 1985).
- trypanosomes enter the mammalian host through a tsetse bite, they start to proliferate as long slender bloodstream forms. While the disease progresses, more and more trypanosomes are converted to short stumpy forms that are unable to proliferate but in contrast to the long slender forms can be transmitted to a new tsetse fly. In the fly, the trypanosomes go through some further developmental stages before they are passed on to a new mammalian host.
- trypanosomes In order to find alternative treatments, purine metabolism has for a long time been a hot subject in the field of trypanosomes and related organisms (reviewed in Hassan, H. F. and Coombs, G. H. (1988) FEMS Microbiol. Rev. 54, 47-84). It has previously been established that trypanosomes lack the ability to form purines de novo and therefore need hypoxanthine, adenine or guanine which are salvaged through various phosphoribosyltransferases. Any of these three bases is fine since the trypanosomes, like most organisms, have all the enzymes needed to interconvert IMP, AMP and GMP.
- the trypanosomes do not have any salvage pathway for CTP synthesis. Instead, CTP is only synthesized de novo.
- the invention relates to the use of a CTP synthetase inhibitor in the manufacture of a medicament for the treatment of a disease caused by any parasitic protozoa wherein CTP is synthesized de novo by CTP synthetase.
- a CTP synthetase inhibitor in the form a glutamine analogue is used, in which case a further component may be used to suppress toxic effects thereof that may harm the patient who is given the medicament.
- the present invention provides for the first time a non-toxic and cost-effective medicament.
- Fig 6 shows proliferation of BALB/c fibroblasts with increasing DON concentrations in the absence (squares) or presence of 10 ⁇ M (diamonds) of 160 ⁇ M hypoxanthine (triangles).
- the fibroblasts were seeded at a density so low that they could not get confluent within three days. When they had settled on the plates, they were exposed to the drugs and left for three days. At this point the amount of cells was indirectly counted by a method described in the section "Material and methods" below.
- the proliferation index on the ordinata shows the relative amount of cells as compared to the sample without drug.
- RNA and DNA 200 ml trypanosomes in logarithmic growth phase were collected by centrifugation (2 min. at 3000 RPM) and resuspended in 20 ml cultivation medium. After 30 min. preincubation at 37°C and 7% CO 2 , they were given a final concentration of 0.13 ⁇ M 39Ci/mmol [5,6-3H]-uracil (Moravek Biochemicals Inc.) and incubated for various amounts of time.
- 6-diazo-5-oxo-L-norleucine (DON), acivicin and azaserine were bought from Sigma. They were dissolved in water and stored as 5 mM solutions at -20 °C. Cyclopentenyl cytosine was a kind gift from Grant McClarty at the Dept. of Medical Microbiology, University of Manitoba, 730 William Ave, Winnipeg, Manitoba R3E OW3, Canada. It was stored as a 50 mM solution in dimethyl sulfoxide (DMSO) at 4°C. The final concentration of DMSO in the growth media of the trypanosomes never became more than 0.5% and that had no effect on the NTP pools or the proliferation of the parasites.
- DMSO dimethyl sulfoxide
- hypoxanthine could relieve the proliferation block on mammalian cells with hypoxanthine. Ultimately, a combination therapy of DON and hypoxanthine may relieve some of the side effects associated with DON. Since hypoxanthine is naturally occurring in the bloodstream, no severe toxic effects from this compound are expected. Hypoxanthine is known to cross the blood-brain barrier (Cornford, E. M. and Oldendorf, W. H. (1975) Biochim. Biophys. Ada 394, 211-219; and Spector, R. (1987) Neurochem. Res. 12, 791- 796).
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/258,810 US7157449B2 (en) | 2000-04-27 | 2001-04-20 | Medicament for the treatment of diseases caused by parasitic protozoa |
EP01924057A EP1284725B1 (en) | 2000-04-27 | 2001-04-20 | Medicament for the treatment of diseases caused by parasitic protozoa |
DE60132581T DE60132581T2 (en) | 2000-04-27 | 2001-04-20 | MEDICAMENT FOR THE TREATMENT OF DISORDERS CAUSED BY PARASITIC PROTOCOLS |
AU2001250722A AU2001250722A1 (en) | 2000-04-27 | 2001-04-20 | Medicament for the treatment of diseases caused by parasitic protozoa |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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SE0001531-3 | 2000-04-27 | ||
SE0001531A SE0001531D0 (en) | 2000-04-27 | 2000-04-27 | Medication for the treatment of diseases caused by parasitic protozoa |
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Publication Number | Publication Date |
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WO2001080809A2 true WO2001080809A2 (en) | 2001-11-01 |
WO2001080809A3 WO2001080809A3 (en) | 2002-02-28 |
Family
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---|---|---|---|
PCT/SE2001/000864 WO2001080809A2 (en) | 2000-04-27 | 2001-04-20 | Medicament for the treatment of diseases caused by parasitic protozoa |
Country Status (8)
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US (1) | US7157449B2 (en) |
EP (1) | EP1284725B1 (en) |
AT (1) | ATE384521T1 (en) |
AU (1) | AU2001250722A1 (en) |
DE (1) | DE60132581T2 (en) |
ES (1) | ES2298229T3 (en) |
SE (1) | SE0001531D0 (en) |
WO (1) | WO2001080809A2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014186435A2 (en) * | 2013-05-14 | 2014-11-20 | University Of Georgia Research Foundation, Inc. | Compositions and methods for reducing neointima formation |
WO2016201307A1 (en) * | 2015-06-12 | 2016-12-15 | The United State of America, as represented by the Secretary, Dept. of Health and Human Services | Glutamine antagonists for use in treating cerebral edema and cerebral malaria |
Families Citing this family (1)
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WO2007001395A2 (en) * | 2004-10-04 | 2007-01-04 | University Of South Carolina | Prevention and treatment of influenza with glutamine antagonist agents |
Citations (1)
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WO1998031375A1 (en) * | 1997-01-21 | 1998-07-23 | The United States Of America As Represented By Thesecretary Of The Department Of Health And Human Sevices | Enhanced suppression of hiv-1 by the combination of cytidine nucleoside analogues and ctp synthase inhibitors |
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WO1991000081A2 (en) * | 1989-06-21 | 1991-01-10 | The Catholic University Of America | Anti-malarial composition and method of use |
US5180714A (en) * | 1990-10-31 | 1993-01-19 | Health Research, Inc. | Adenosine compounds for the treatment of diseases caused by parasitic protozoa |
US5776718A (en) * | 1995-03-24 | 1998-07-07 | Arris Pharmaceutical Corporation | Reversible protease inhibitors |
US6025335A (en) * | 1995-09-21 | 2000-02-15 | Lipitek International, Inc. | L-Nucleoside Dimer Compounds and therapeutic uses |
-
2000
- 2000-04-27 SE SE0001531A patent/SE0001531D0/en unknown
-
2001
- 2001-04-20 AT AT01924057T patent/ATE384521T1/en not_active IP Right Cessation
- 2001-04-20 ES ES01924057T patent/ES2298229T3/en not_active Expired - Lifetime
- 2001-04-20 EP EP01924057A patent/EP1284725B1/en not_active Expired - Lifetime
- 2001-04-20 DE DE60132581T patent/DE60132581T2/en not_active Expired - Lifetime
- 2001-04-20 AU AU2001250722A patent/AU2001250722A1/en not_active Abandoned
- 2001-04-20 WO PCT/SE2001/000864 patent/WO2001080809A2/en active IP Right Grant
- 2001-04-20 US US10/258,810 patent/US7157449B2/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998031375A1 (en) * | 1997-01-21 | 1998-07-23 | The United States Of America As Represented By Thesecretary Of The Department Of Health And Human Sevices | Enhanced suppression of hiv-1 by the combination of cytidine nucleoside analogues and ctp synthase inhibitors |
Non-Patent Citations (4)
Title |
---|
KENNETH E. KINNAMON ET AL.: 'Activity of anticancer compounds against trypanosoma cruzi-infected mice' AM. J. TROP. MED. HYG. vol. 58, no. 6, 1998, pages 804 - 806, XP002945509 * |
KIM E. NICHOLS ET AL.: 'Monocytoid differentiation of freshly isolated human myeloid leukemia cells and HL-60 cells induced by the glutamine antagonist acivicin' BLOOD vol. 74, no. 5, October 1989, pages 1728 - 1737, XP002945510 * |
TAKASHI AOKI ET AL.: 'Quantitative determination of trypanosoma cruzi growth inside host cells in vitro and effect of allopurinol' PURINE AND PYRIMIDINE METABOLISM IN MAN VIII/EDITED BY AMRIK SAHOTA AND MILTON W. TAYLOR. NEW YORK PLENUM PRESS COP. (ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY, 0065-2598; 370) 1994, pages 499 - 502, XP002945508 * |
TANMOY MUKHERJEE ET AL.: 'Acivicin: A highly active potential chemotherapeutic agent against visceral leishmaniasis' BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS vol. 170, no. 2, July 1990, pages 426 - 432, XP002945507 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014186435A2 (en) * | 2013-05-14 | 2014-11-20 | University Of Georgia Research Foundation, Inc. | Compositions and methods for reducing neointima formation |
WO2014186435A3 (en) * | 2013-05-14 | 2015-02-19 | University Of Georgia Research Foundation, Inc. | Compositions, medical devices and grafts comprising ctp synthase 1 inhibitors and their use for reducing neointima formation |
US10328182B2 (en) | 2013-05-14 | 2019-06-25 | University Of Georgia Research Foundation, Inc. | Compositions and methods for reducing neointima formation |
US11246965B2 (en) | 2013-05-14 | 2022-02-15 | University Of Georgia Research Foundation, Inc. | Compositions and methods for reducing neointima formation |
WO2016201307A1 (en) * | 2015-06-12 | 2016-12-15 | The United State of America, as represented by the Secretary, Dept. of Health and Human Services | Glutamine antagonists for use in treating cerebral edema and cerebral malaria |
Also Published As
Publication number | Publication date |
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DE60132581T2 (en) | 2009-01-29 |
SE0001531D0 (en) | 2000-04-27 |
EP1284725A2 (en) | 2003-02-26 |
EP1284725B1 (en) | 2008-01-23 |
AU2001250722A1 (en) | 2001-11-07 |
ATE384521T1 (en) | 2008-02-15 |
WO2001080809A3 (en) | 2002-02-28 |
DE60132581D1 (en) | 2008-03-13 |
US7157449B2 (en) | 2007-01-02 |
US20030109505A1 (en) | 2003-06-12 |
ES2298229T3 (en) | 2008-05-16 |
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