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 PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- depression
- coait
- drugs
- disease
- inhibit
- Prior art date
Links
- 101001074429 Bacillus subtilis (strain 168) Polyketide biosynthesis acyltransferase homolog PksD Proteins 0.000 title description 3
- 101000936617 Bacillus velezensis (strain DSM 23117 / BGSC 10A6 / FZB42) Polyketide biosynthesis acyltransferase homolog BaeD Proteins 0.000 title description 3
- 229940001470 psychoactive drug Drugs 0.000 title description 2
- 239000004089 psychotropic agent Substances 0.000 title description 2
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 title 1
- 229940093530 coenzyme a Drugs 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 24
- 229940079593 drug Drugs 0.000 claims abstract description 18
- 208000020016 psychiatric disease Diseases 0.000 claims abstract description 9
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 claims description 40
- 229940114079 arachidonic acid Drugs 0.000 claims description 20
- 235000021342 arachidonic acid Nutrition 0.000 claims description 20
- 201000000980 schizophrenia Diseases 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 9
- 208000020925 Bipolar disease Diseases 0.000 claims description 8
- 206010012289 Dementia Diseases 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 208000019901 Anxiety disease Diseases 0.000 claims description 5
- 208000012902 Nervous system disease Diseases 0.000 claims description 5
- 206010041250 Social phobia Diseases 0.000 claims description 5
- 230000036506 anxiety Effects 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- 208000025966 Neurological disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 206010015037 epilepsy Diseases 0.000 claims description 4
- 239000012190 activator Substances 0.000 claims description 2
- 230000028709 inflammatory response Effects 0.000 claims 4
- 208000024827 Alzheimer disease Diseases 0.000 claims 3
- 208000018737 Parkinson disease Diseases 0.000 claims 3
- 208000020401 Depressive disease Diseases 0.000 claims 2
- 238000001228 spectrum Methods 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 206010061218 Inflammation Diseases 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 150000003904 phospholipids Chemical class 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 102000015696 Interleukins Human genes 0.000 description 4
- 108010063738 Interleukins Proteins 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 230000008105 immune reaction Effects 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229940047122 interleukins Drugs 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 208000028683 bipolar I disease Diseases 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 229940047124 interferons Drugs 0.000 description 2
- 150000002617 leukotrienes Chemical class 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical group C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- QBRNQTJKAVFRKA-UHFFFAOYSA-N 1-(7-ethylnonyl)-3,4,5-triphenylimidazol-2-one;phosphoric acid Chemical compound OP(O)(O)=O.C=1C=CC=CC=1N1C(=O)N(CCCCCCC(CC)CC)C(C=2C=CC=CC=2)=C1C1=CC=CC=C1 QBRNQTJKAVFRKA-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- FKJSFKCZZIXQIP-UHFFFAOYSA-N 2-bromo-1-(4-bromophenyl)ethanone Chemical compound BrCC(=O)C1=CC=C(Br)C=C1 FKJSFKCZZIXQIP-UHFFFAOYSA-N 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 108700016155 Acyl transferases Proteins 0.000 description 1
- 102000057234 Acyl transferases Human genes 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-M Arachidonate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC([O-])=O YZXBAPSDXZZRGB-DOFZRALJSA-M 0.000 description 1
- 206010011953 Decreased activity Diseases 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- MQUQNUAYKLCRME-INIZCTEOSA-N N-tosyl-L-phenylalanyl chloromethyl ketone Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](C(=O)CCl)CC1=CC=CC=C1 MQUQNUAYKLCRME-INIZCTEOSA-N 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 description 1
- 229940114078 arachidonate Drugs 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000003943 catecholamines Chemical group 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000002329 esterase inhibitor Substances 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- JMZFEHDNIAQMNB-UHFFFAOYSA-N m-aminophenylboronic acid Chemical compound NC1=CC=CC(B(O)O)=C1 JMZFEHDNIAQMNB-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- HCZKYJDFEPMADG-UHFFFAOYSA-N nordihydroguaiaretic acid Chemical compound C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000024715 positive regulation of secretion Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- MHOZZUICEDXVGD-UHFFFAOYSA-N pyrrolo[2,3-d]imidazole Chemical class C1=NC2=CC=NC2=N1 MHOZZUICEDXVGD-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000007814 response to vitamin B3 Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 108020002447 serine esterase Proteins 0.000 description 1
- 102000005428 serine esterase Human genes 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003595 thromboxanes Chemical class 0.000 description 1
- 150000003952 β-lactams Chemical class 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
-
- 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.
Landscapes
- 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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9904895.1A GB9904895D0 (en) | 1999-03-03 | 1999-03-03 | Regulators of coenzyme-A-independent transacylase as psychotropic drugs |
| GB9904895.1 | 1999-03-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2000051684A2 true WO2000051684A2 (fr) | 2000-09-08 |
| WO2000051684A3 WO2000051684A3 (fr) | 2001-01-04 |
Family
ID=10848886
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)
| Country | Link |
|---|---|
| GB (1) | GB9904895D0 (fr) |
| WO (1) | WO2000051684A2 (fr) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0289204B1 (fr) * | 1987-04-27 | 1991-07-17 | 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 |
| EP0841910A4 (fr) * | 1995-07-25 | 2006-09-13 | Smithkline Beecham Corp | INHIBITION D'UNE TRANSACYLASE INDEPENDANTE DE LA COENZYME A (CoA) ET APOPTOSE |
| AU731692C (en) * | 1996-10-11 | 2001-10-11 | Scarista Limited | Pharmaceutical preparation comprising eicosapentaenoic acid and/or stearidonic acid |
| AU7222598A (en) * | 1997-04-29 | 1998-11-24 | Scotia Holdings Plc | Treatment of depression and anxiety using docosahexaenoic acid or natural antioxidants |
-
1999
- 1999-03-03 GB GBGB9904895.1A patent/GB9904895D0/en not_active Ceased
-
2000
- 2000-03-03 WO PCT/GB2000/000779 patent/WO2000051684A2/fr active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| GB9904895D0 (en) | 1999-04-28 |
| WO2000051684A3 (fr) | 2001-01-04 |
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