Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
1996-09-10
1998-12-29
Richter, Johann
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
514462, 549345, 435171, C12D 1704, A16K 3134, C07D30794
Patent
active
058540369
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns novel compounds obtained by fermenting a microorganism of the genus Memnoniella or Stachybotrys, which compounds are inhibitors of the enzyme inositol monophosphatase (EC 3.1.3.25), hereinafter referred to with the acronym "IMPase".
The present invention also relates to the use of these novel compounds in the treatment of mania and depression symphtoms and pharmaceutical formulations comprising said compounds as active ingredient; the compounds of the invention may also be used in analythical methods for detecting IMPase.
The invention is also concerned with the fermentation and purification process by which the novel compounds are obtained.
Lithium, preferably employed in the form of lithium carbonate, is highly specific in alleviating manic symptoms, normalizing the mood of manic patients rather than compensating the excesses of the manic state through sedation or "tranquillization". Furthermore, it seems to be the only drug in psychiatry for which clear prophylaxis against disease recurrences and deterioration has been demonstrated. Lithium shows its clearest effects in bipolar disorders, which include both mania and depression, or only mania; these disorders are subdivided into Bipolar I and II disorders. In the former cases, there is presence of a full-blown manic episode, while in the latter case there is mild hypomania only.
Despite its therapeutic properties, a number of issues detract from the therapeutic utility of lithium. Antipsychotic drugs are the first pharmacologic mode of treatment of acute bipolar disorder, unless the patient is manageable enough to wait the 7-10 days it takes for lithium to exert its antimanic effect. A costly prelithium workup is required because of the adverse effects common to lithium therapy. As a matter of fact, lithium can cause a transient leukocytosis, can cause patients with a borderline thyroid reserve to become clinically hypothyroid, and can decompensate cardiac status due to shifts in fluids and electrolytes.
It has been observed that the polyuria-polydipsia syndrome occurs in up to 60% of treated patients. Structural lesions in kidney, such as interstitial fibrosis, tubular atrophy and glomerular sclerosis, are reported after chronic lithium treatment, especially in patients who have experienced lithium toxicity. Other adverse effects of lithium include tremor, weight gain, diarrhea and skin rash. These side effects are serious practical deterrents to the use of lithium in clinical practice.
Side effects, especially the more serious ones, can be reduced by monitoring plasma lithium concentrations in bipolar patients. The need to monitor plasma drug concentrations, and to maintain these within a narrow therapeutic range, destract from its clinical utility.
An ideal lithium mimetic agent would have a rapid onset of action in both bipolar and non-bipolar depression, require only once-a-day dosing, and have a safety profile requiring no extensive pretreatment medical evaluation, no plasma drug monitoring, nor be associated with as severe a spectrum of side effects as lithium, per se.
It was demonstrated that inositol monophosphatase is a key enzyme in the phosphoinositide cycle and is responsible for the provision of inositol by dephosphorylation of inositol-1-phosphate, inositol-3-phosphate, and inositol-4-phosphate; as lithium inhibits the activity of said enzyme, it has been suggested that this inhibition is likely to be the molecular mechanism by which lithium exerts its anti-manic and anti-depressive activity.
In this view, development of potent and specific inhibitors of IMPase, could lead to completely novel drugs effective for the treatment of mania and depression.
A compound of formula I, ##STR1## which shows the above IMPase-inhibiting activity, was obtained by fermenting a fungus of the specie Memnoniella or Stachybotrys as described in U.S. Pat No. 4,981,980. Such compound is also described by Y. K. T. Lam et al. in Jour. of Antib., vol. 45, 9, 1992, pp. 1397-1403, where it is named L-671,776. The above structure seems
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Denaro Maurizio
Ferrari Pietro
Islam Khalid
Sponga Federica
Stefanelli Stefania
Gruppo Lepetit S.p.A.
Homan Ruth E.
Richter Johann
Solola Taofiq A.
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