Recent Patents on CNS Drug Discovery (Discontinued) - Volume 2, Issue 1, 2007

Adenosine A2A receptors are highly concentrated in the striatum, where they play an important modulatory role of glutamatergic transmission to the GABAergic enkephalinergic neuron, which function is particularly compromised in Parkinson's disease and in the early stages of Huntington's disease. An important amount of preclinical data suggested the possible application of A2A receptor antagonists in Parkinson's disease, particularly as adjuvant therapy to the currently used dopaminergic agonists. Several A2A receptor antagonists are currently in clinical trials in patients with Parkinson's disease and initial results have been promising. In recent years, many pharmaceutical companies have started programs to develop A2A antagonists for Parkinson’s disease and for other indications, such as neurodegenerative diseases in general, depression and restless legs syndrome. Antagonists with high A2A receptor affinity and selectivity have been developed from various chemical classes of compounds, including xanthines, adenines and other amino-substituted heterocyclic compounds. Novel structures include benzothiazole and thiazolopyridine derivatives. The present review describes properties of standard A2A receptor antagonists including those in clinical development. Furthermore, the different chemical classes of A2A receptor antagonists that have been described in the literature, including recent patent literature, will be presented.

Alcohol abuse produces damaging effects on the CNS that leads to several types of disorders. When consumed during pregnancy, alcohol may cause craniofacial malformations, growth retardation and brain damage in offspring. These symptoms are grouped by the term fetal alcohol syndrome (FAS). FAS is the most common cause of non-genetic mental retardation in the western world. Substantial efforts to elucidate the molecular basis of these impairments are currently in progress. Whereas FAS is totally preventable by avoiding alcohol intake during pregnancy, efficient therapies to prevent or mitigate the effects of prenatal alcohol exposure are still not available but many pharmacological treatments have been developed to avoid alcohol intake and dependence in adults. The present article reviews the most relevant mechanisms of alcohol injury in developing brain and the strategies and patents that are currently available and in progress to prevent therapy for FAS.

The description of mental illness states brings into light a referential paradox on the absence of grounds for normality. Furthermore, the semiology itself poses a problem throughout the intricate consensual relations between psychiatrists. New molecules with activity on the CNS are ever more specific as to molecular cognitive capabilities, reaching limits of individual genetic variability. Cultural mechanisms of neuronal adaptation also contribute significantly to representations and its correlation with feelings. Neuropeptides increase excitability in various different brain regions, with networks underlying optimal behaviour patterns. Therefore, the sole specification of target molecules yet does not lead directly to specific results, as insights from a systematic approach should conceal. Current validation methods generate insufficient data for discriminating successful treatable candidates. Instead of regarding the heuristics of empirically classified disease models, a new tendency to compromise scientia rationale with technical capabilities should be regarded. Some of the drugs that have obtained patents recently will be discussed in the framework of their rational and actual specificity. The molecular basis underlining function will be contrasted with an alternative approach, namely: how functional organization constrains molecular action. The categories comprising neurogenarative pathologies at one hand and the mood disorders at the other hand will be analysed separately as the procedures guiding drug design in each case seem to be different.

Despite widespread use and validation of their efficacy, about 40-60% of obsessive compulsive disorder (OCD) sufferers do not respond to appropriate courses of treatment with serotonin reuptake inhibitors (SRI) and even with the combination of pharmacotherapy and cognitive behaviour therapy a substantial number of patients remain dramatically symptomatic. Recently, there has been increasing interest in investigating glutamatergic dysfunction in OCD. Multiple lines of evidence point toward glutamatergic dysfunction being related to the pathophysiology of OCD, with glutamate modulating drugs being an alternative pharmacological strategy for treating OCD. In this article we focus in detail on the rationale for targeting glutamatergic agents as well as review the recent important patents for compounds that have emerged from these studies.

Voltage gated sodium channels play important roles both in vital physiological functions and several pathological processes of the central nervous system. Epilepsy, chronic pain, neurodegenerative diseases, and spasticity are all characterized by an over-excited state of specific groups of central neurons that is accompanied by an abnormally increased activity of sodium channels. An efficient strategy of controlling such diseases is to use blockers that preferentially act on these over-excited cells. State dependently acting agents, such as phenytoin, or lamotrigine, leave normal physiological functions relatively intact, resulting in a favorable therapeutic window. Nine isoforms of the channel forming alpha subunit are known, which show distinct expression patterns in different tissues. Another possible way to decrease the chance of adverse effects is to develop agents selectively inhibiting the channel subtype involved in the pathomechanism of the disease to be treated. Many recent patents claim sodium channel blockers with improved characteristics regarding state dependency or subtype selectivity. Such agents may offer a breakthrough in the treatment of a variety of central nervous system diseases. This review focuses on the current trends in sodium channel research, surveying the traditional and newly emerging therapeutic fields, and the diverse medicinal chemistry of sodium channel blockers.

The neurokinin (NK) receptor family has been proposed as targets for neural-related diseases. The experimental studies indicate that this family of receptors might also be targets for malignancies, both solid and hematological tumors. However, an understanding of the biology of other rmolecules with sequence similarity to NK receptors is required. Of significance is the HGFIN gene that shares structural homology with NK1. Through this homology, the HGFIN interacts with the high affinity ligand of NK1, substance P. This report discusses potential applications for targets against NK receptors, and the role of HGFIN in drug designs. This review is relevant for central and peripheral nervous system drug development, and also cancer drugs for breast and neuroblastoma. The potential for leukemia drugs and Patents are also discussed