WO2000051684A2

WO2000051684A2 - Regulators of coenzyme-a-independent transacylase as psychotropic drugs

Info

Publication number: WO2000051684A2
Application number: PCT/GB2000/000779
Authority: WO
Inventors: David Frederick Horrobin
Original assignee: Scarista Ltd
Current assignee: Scarista Ltd
Priority date: 1999-03-03
Filing date: 2000-03-03
Publication date: 2000-09-08
Anticipated expiration: 2001-09-03
Also published as: GB9904895D0; WO2000051684A3

Abstract

Use of drugs which are able to inhibit CoAIT in the treatment of, or in the manufacture of a medicament for the treatment of psychiatric disorders.

Description

REGULATORS OF COENZYME-A-INDEPENDENT TRANSACYLASE AS PSYCHOTROPIC DRUGS

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.

Surprisingly, in terms of effectiveness, there is little evidence that the drugs now used in these psychiatric disorders work any better than the ones which were introduced over 40 years ago. What improvements there have been are related almost entirely to reductions in side effects rather than to improvements in efficacy. In view of this long record of failure to improve efficacy, it is clear that drugs with novel mechanisms of action are required to treat psychiatric disorders. This patent specification proposes an entirely new target for drugs which will treat depression, and also for drugs which will treat any other psychiatric or neurological disorder including anxiety, panic, schizophrenia, manic-depression, social phobia, epilepsy and any other disease affecting the nervous system.

One of the observations which has emerged in recent years in relation to depression is that patients often exhibit activation of macrophages and of mononuclear cells which are involved in immune reactions and in inflammation (Smith RS, Medical Hypotheses 1991 : 35:298-306: Maes M, Smith RS Biological Psychiatry 1998; 43:313-4; Maes M, Smith R, Scharpe S Psychoneuroendocrinology 1995; 20: 1 1 1-6; Leonard BE, Song C Pharmacology and Biochemistry of Behaviour 1996; 54:299-303). As a result, many depressed patients have elevated circulating levels of interleukins, interferons and other cytokines. These latter molecules, when used for the treatment of patients with multiple sclerosis or cancer, frequently produce very severe depression. The activation of the macrophage/lymphocyte system may therefore be playing a fundamental role in the causation of depression. It may be particularly important in the depression associated with cancer since in many patients with cancer circulating levels of interleukins and other cytokines are strikingly elevated. It may also be important in the depression associated with dementia and aging since brain interleukin levels are elevated in aging and dementia.

The biochemical reason for this activation is unknown. I propose that it is due to overactivity of the enzyme CoAIT which plays a fundamental role in regulating the production of pro-inflammatory mediators.

Arachidonic acid (AA) 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.

There are many different compartments inside the cell where arachidonic acid may be found. However, evidence has been accumulating to the effect that one particular compartment plays a central role in inflammation. This compartment is the one which is filled by AA under the influence of the enzyme Coenzyme- A-independent transacylase (CoAIT) (JD Winkler et al, Journal of Pharmacology and Experimental Therapeutics 1995; 274: 1338-47; JD Winkler & FH Chilton pp 147-171 in Inflammation: Mediators and Pathways. Ed RR Ruffolo & MA Hollinger, CRC Press, Boca Raton, 1995). 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. These 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.

One characteristic of people with depression, in addition to the elevations of cytokines, is that levels of arachidonate in plasma and red cells are relatively high. This AA is available for signalling purposes because concentrations of prostaglandin and thromboxane derivatives of AA are also high in plasma, saliva and cerebrospinal fluid (PB Adams et al, Lipids 1996; 31:5157-5161; R Edwards et al, Journal of Affective Disorders 1998; 48:149-155; JR Calabrese et al, Psychiatry Research, 1986; 17:41-47; J Lieb et al, Prostaglandins, Leukotrienes and Medicine 1983; 10:361-7; S Nishiino et al, -American Journal of Psychiatry 1989; 146-365-8; M Linnoila et al, -Archives of General Psychiatry 1983; 40:405-6).

No explanation for these elevated AA and prostaglandin levels is known. However, I propose that they are a consequence of increased CoAIT activity which transfers AA to cell signalling compartments involved in mounting inflammatory, immunological and cytokine responses. I further propose that inhibition of CoAIT will be an effective novel treatment for depression and for closely related conditions like anxiety, panic, social phobia and bipolar disorder. I also propose that agents which can compete with arachidonic acid for the CoAIT active site and which can be transferred to recipient lysophospholipids but then converted to less pro-inflammatory agents are effective as antidepressants. Fatty acids and fatty acid derivatives which can compete with arachidonic acid are candidate compounds. 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). Other compounds which can inhibit CoAIT are p-bromophenacyl bromide, nordihydroguaretic acid and several groups of compounds being developed by the pharmaceutical industry. These compounds include ones such as SKαF98625 (diethyl 7-(3,4,5-triphenyl- 2-oxo-2,3-dihydro-imidazol-l-yl)heptane-phosphate) and SKαF 45905 (2-[2-[3- (4-c--doro-3-trifluoro-methylphenyl)ureido]-4,5-dichlorobenzenesulfonic acid inhibitors) (JD Winkler et al, Journal of Pharmacology and Experimental Therapeutics 1995; 274:1338-1347). Other inhibitors which have been described include SKαF 105809 (2-(4-methylsulfιnylphenyl)-3-(4-pyridyl)-6,7- dihydro-[5H]-pyrrolol[l,2-a]imidazole), SKαF 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-[(isobutenyloxy)-3- triphenylmethylamino)]azetidin-2-one). These drugs, and any other related or unrelated compounds which are able to inhibit CoAIT will be effective antidepressants, provided that they can reach the necessary compartments, which may be in the brain, in adequate concentrations.

Whereas in disorders characterised by depression, CoAIT is overactive, in schizophrenia it is underactive. In schizophrenia, 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.

Part of the inflammatory system which is important in psychiatric and neurological disorders is that represented by the microglia of the brain. It will therefore be important to have 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.

Claims

1. A method of treating depression or bipolar disorder by the use of drugs which are able to inhibit CoAIT.

2. A method of treating anxiety, panic, social phobia or any other psychiatric disorder by the use of drugs which are able to inhibit CoAIT.

3. A method of treating neurological disorders where depression may be a feature, including Parkinson's disease, epilepsy and Alzheimer's disease and other dementias by the use of drugs which are able to inhibit CoAIT.

4. A method of treating depression in patients with cancer by the use of drugs which are able to inhibit CoAIT.

5. A method of treating depression in anyone over the age of 60 or in anyone at any age suffering from any form of dementia by the use of drugs which are able to inhibit CoAIT.

6. A method according to any of claims 1 to 5 in which the drug comprises a compound which can be transferrd to lysophospholipids in competition with arachidonic acid, but which produces a smaller inflammatory response than arachidonic acid or no inflammatory response.

7. The use of a CoAIT inhibitor in the preparation of a medicament for the treatment of depression, bipolar disorder; anxiety, panic, social phobia or any other psychiatric disorder; neurological disorders where depression may be a feature, including Parkinson's disease, epilepsy and Alzheimer's disease and other dementias; depression in patients with cancer; or depression in anyone over the age of 60 or in anyone at any age suffering from any form of dementia.

8. The use of a compound which can be transferrd to lysophospholipids in competition with arachidonic acid, but which produces a smaller inflammatory response than arachidonic acid or no inflammatory response in the preparation of a medicament for the treatment of depression, bipolar disorder; anxiety, panic, social phobia or any other psychiatric disorder; neurological disorders where depression may be a feature, including Parkinson's disease, epilepsy and Alzheimer's disease and other dementias; depression in patients with cancer; or depression in anyone over the age of

60 or in anyone at any age suffering from any form of dementia.

9. A method of treating schizophrenia or related schizophrenia-spectrum disorders by the use of drugs which are able to activate CoAIT.

10. Use of a CoAIT activator in the preparation of a medicament for the treatment of schizophrenia or related schizophrenia-spectrum disorders.