WO2000051684A2 - Regulateurs de transacylase independante de la coenzyme a comme medicaments psychotropes - Google Patents

Regulateurs de transacylase independante de la coenzyme a comme medicaments psychotropes Download PDF

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Publication number
WO2000051684A2
WO2000051684A2 PCT/GB2000/000779 GB0000779W WO0051684A2 WO 2000051684 A2 WO2000051684 A2 WO 2000051684A2 GB 0000779 W GB0000779 W GB 0000779W WO 0051684 A2 WO0051684 A2 WO 0051684A2
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WO
WIPO (PCT)
Prior art keywords
depression
coait
drugs
disease
inhibit
Prior art date
Application number
PCT/GB2000/000779
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English (en)
Other versions
WO2000051684A3 (fr
Inventor
David Frederick Horrobin
Original Assignee
Scarista Limited
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 Scarista Limited filed Critical Scarista Limited
Publication of WO2000051684A2 publication Critical patent/WO2000051684A2/fr
Publication of WO2000051684A3 publication Critical patent/WO2000051684A3/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
    • 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

Definitions

  • Schizophrenia depression and bipolar disorder (manic-depression) are the major common psychiatric disorders. Schizophrenia is usually treated by drugs which block dopamine and serotonin receptors. Bipolar disorder is usually treated by lithium or by one of a range of drugs which also have anti-epileptic actions. Depression is usually treated by drugs which in some way modify catecholamine or serotonin function or metabolism.
  • Arachidonic acid is generally recognised as playing a major role in immune and inflammatory reactions. In the process of many such reactions AA is released from a phospholipid compartment. The released AA may act by itself or may be converted to a range of prostaglandin, leukotriene, or other oxygenated metabolites. This range of substances is fundamental to a normal immune response and to the stimulation of secretion of interleukins, interferons and other cytokines.
  • CoAIT transfers AA from other phospholipids to particular phospholipids, usually ones with an ether linkage at the Snl position, which are the sources of the AA released during activation of macrophages, lymphocytes, polymorphonuclear leucocytes and other cells of the inflammation and immune systems.
  • the donor phospholipids are often but not always phosphatidylcholines with an AA group at the Sn2 position and an acyl-link to another fatty acid at the Snl position.
  • the recipient phospholipids are usually lysophospholipids from which the fatty acid at the Sn2 position has been removed.
  • lysphospholipids often have an alkyl or an alkenyl group at the Snl position, and are also often of the phosphatidyl ethanolamine class.
  • the recipient phospholipids become enriched in AA which is then released during immune and inflammatory reactions.
  • CoAIT inhibitors have recently been developed as anti-inflammatory agents but have not been proposed to have anti-depressant actions.
  • Several different classes of compound have been reported to inhibit CoAIT. They include agents which interact with cysteine, serine esterase inhibitors such as phenyl-methyl- sulfonyl fluoride and N-tosyl-L-phenylalanine chloromethyl ketone, p- nitrophenyl phosphate and M-aminophenyl boronic acid, and agents which can inhibit the enzyme lecithin choline acyltransferase which has a similar mode of action to CoAIT (Winkler & Chilton, 1995).
  • SK ⁇ F98625 diethyl 7-(3,4,5-triphenyl- 2-oxo-2,3-dihydro-imidazol-l-yl)heptane-phosphate
  • SK ⁇ F 45905 2-[2-[3- (4-c--doro-3-trifluoro-methylphenyl)ureido]-4,5-dichlorobenzenesulfonic acid inhibitors
  • inhibitors which have been described include SK ⁇ F 105809 (2-(4-methylsulf ⁇ nylphenyl)-3-(4-pyridyl)-6,7- dihydro-[5H]-pyrrolol[l,2-a]imidazole), SK ⁇ F 105561 (2-(4-methylthiophenyl)- 3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolol[l,2-a]imidazole and other pyrroloimidazoles (PJ Marshall et al, Biochemical Pharmacology 1991 ; 42: 813-824) and a range of beta-lactam derivatives, including SB 212047 (4- methoxbenzyl(3S,4R)-6-bromo-6-[(l-methyl-l,2,3-triazol-4-yl)- hydroxymethyljpenicillanate) and SB216754 ((3S, 4R)-4-[(isobuteny
  • CoAIT is overactive, in schizophrenia it is underactive.
  • immune and inflammatory reactions are impaired (DF Horrobin et al, Schizophrenia Research 1994; 13:195-207), and the response to niacin, which activates arachidonic acid release, is seriously defective (P Ward et al, Schizophrenia Research 1998; 29:269-274).
  • Drugs which activate CoAIT will therefore be important and effective in schizophrenia.
  • CoAIT inhibitors or activators which can penetrate the brain.
  • One way of dong this is to make them more lipophilic. This can be done by attaching to them fatty acids with 12-30 carbon atoms and 0-6 double bonds. It can also be done by incorporating them into compounds such as these described in international patent applications WO 96/34846 and WO 96/34855.

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

Abstract

L'invention concerne l'utilisation de médicaments capables d'inhiber une transacylase indépendante de la coenzyme A dans le traitement ou la production d'un médicament destiné au traitement de troubles psychiatriques.
PCT/GB2000/000779 1999-03-03 2000-03-03 Regulateurs de transacylase independante de la coenzyme a comme medicaments psychotropes WO2000051684A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9904895.1 1999-03-03
GBGB9904895.1A GB9904895D0 (en) 1999-03-03 1999-03-03 Regulators of coenzyme-A-independent transacylase as psychotropic drugs

Publications (2)

Publication Number Publication Date
WO2000051684A2 true WO2000051684A2 (fr) 2000-09-08
WO2000051684A3 WO2000051684A3 (fr) 2001-01-04

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/000779 WO2000051684A2 (fr) 1999-03-03 2000-03-03 Regulateurs de transacylase independante de la coenzyme a comme medicaments psychotropes

Country Status (2)

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GB (1) GB9904895D0 (fr)
WO (1) WO2000051684A2 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289204A2 (fr) * 1987-04-27 1988-11-02 Efamol Holdings Plc Compositions pharmaceutiques contenant des sels de lithium
WO1993016674A1 (fr) * 1992-02-11 1993-09-02 Smithkline Beecham Corporation INHIBITEURS DE LA CoA-IT ET DU PAF
WO1997004765A1 (fr) * 1995-07-25 1997-02-13 Smithkline Beecham Corporation INHIBITION D'UNE TRANSACYLASE INDEPENDANTE DE LA COENZYME A (CoA) ET APOPTOSE
WO1998016216A1 (fr) * 1996-10-11 1998-04-23 Scotia Holdings Plc Preparation pharmaceutique contenant de l'acide eicosapentanoïque et/ou de l'acide stearidonique
WO1998048788A1 (fr) * 1997-04-29 1998-11-05 Scotia Holdings Plc Traitement de la depression et de l'anxiete au moyen d'acide docosahexaenoique ou d'antioxydants naturels

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289204A2 (fr) * 1987-04-27 1988-11-02 Efamol Holdings Plc Compositions pharmaceutiques contenant des sels de lithium
WO1993016674A1 (fr) * 1992-02-11 1993-09-02 Smithkline Beecham Corporation INHIBITEURS DE LA CoA-IT ET DU PAF
WO1997004765A1 (fr) * 1995-07-25 1997-02-13 Smithkline Beecham Corporation INHIBITION D'UNE TRANSACYLASE INDEPENDANTE DE LA COENZYME A (CoA) ET APOPTOSE
WO1998016216A1 (fr) * 1996-10-11 1998-04-23 Scotia Holdings Plc Preparation pharmaceutique contenant de l'acide eicosapentanoïque et/ou de l'acide stearidonique
WO1998048788A1 (fr) * 1997-04-29 1998-11-05 Scotia Holdings Plc Traitement de la depression et de l'anxiete au moyen d'acide docosahexaenoique ou d'antioxydants naturels

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1989 VADDADI K S ET AL: "A DOUBLE-BLIND TRIAL OF ESSENTIAL FATTY ACID SUPPLEMENTATION IN PATIENTS WITH TARDIVE DYSKINESIA" Database accession no. PREV198988008362 XP002148486 & PSYCHIATRY RESEARCH, vol. 27, no. 3, 1989, pages 313-324, ISSN: 0165-1781 *
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1995 HORROBIN D F ET AL: "Possible relevance of phospholipid abnormalities and genetic interactions in psychiatric disorders: The relationship between dyslexia and schizophrenia." Database accession no. PREV199698702575 XP002148483 & MEDICAL HYPOTHESES, vol. 45, no. 6, 1995, pages 605-613, ISSN: 0306-9877 *
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1995 PEET MALCOLM ET AL: "Depleted red cell membrane essential fatty acids in drug-treated schizophrenic patients." Database accession no. PREV199598430715 XP002148485 & JOURNAL OF PSYCHIATRIC RESEARCH, vol. 29, no. 3, 1995, pages 227-232, ISSN: 0022-3956 *
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1996 ADAMS PETER B ET AL: "Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression." Database accession no. PREV199698797851 XP002148482 & LIPIDS, vol. 31, no. SUPPL., 1996, pages S157-S161, ISSN: 0024-4201 *
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; February 1998 (1998-02) CORRIGAN F M ET AL: "Abnormal content of n-6 and n-3 long-chain unsaturated fatty acids in the phosphoglycerides and cholesterol esters of parahippocampal cortex from Alzheimer's disease patients and its relationship to acetyl CoA content." Database accession no. PREV199800266210 XP002148484 & INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, vol. 30, no. 2, February 1998 (1998-02), pages 197-207, ISSN: 1357-2725 *

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Publication number Publication date
GB9904895D0 (en) 1999-04-28
WO2000051684A3 (fr) 2001-01-04

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