Recent Patents on CNS Drug Discovery (Discontinued) - Volume 5, Issue 3, 2010

Copper is essential for life. It plays a pivotal role in the central nervous system, in which a low concentration of copper results in incomplete development, whereas an excess of copper is injurious. Redox reactions are at the basis of copper toxicity: in fact, it catalyses the production of reactive oxygen species in Fenton or Haber-Weiss reactions. Abnormalities of copper homeostasis in neurodegenerative disorders were discovered decades ago. The steady increase in reports from the literature demonstrating copper involvement in neurodegenerative disorders coincides with the improvement, reliability and low cost devices which measure copper markers in biological samples. These devices also demonstrate increasing relevance in diagnosis and in therapy monitoring as well. Methods and new perspectives for the analysis of copper markers status are discussed herein, weighing pros and cons of application to a specific neurological disorder. In particular, it have been introduced three patents regarding a new apparatus for measuring levels of metal in biological samples, employing a current measuring device. A mention of recent patents concerning new derivatives of curcumin has been done considering its metal chelating and multi-functional properties that make these compounds interesting candidates for treatment of some neurodegenerative disorders.

Transglutaminases are ubiquitous enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Recently, “tissue” transglutaminase, a member of the transglutaminase family of enzymes, has been shown to be involved in the molecular mechanisms responsible for a very widespread human pathology, celiac disease. Transglutaminase activity has also been hypothesized to be involved in the pathogenetic mechanisms responsible for several other human diseases, including neurodegenerative diseases, often associated to celiac disease. Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, supranuclear palsy, Huntington's disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible therapeutic effects of transglutaminase inhibitors and their recent patents for the cure of patients with diseases characterized by aberrant transglutaminase activity and on the strategies to design such transglutaminase inhibitors.

Mitochondrial diseases (MD) are disorders caused by an impairment of the mitochondrial respiratory chain function. They are usually progressive, isolated or multi-system diseases and have variable times of onset. Because mitochondria have their own DNA (mtDNA), MD can be caused by mutations in both mtDNA and nuclear DNA (nDNA). The complexity of genetic control of mitochondrial function is in part responsible for the intra- and inter-familiar clinical heterogeneity of this class of diseases. Despite the remarkable progress in understanding of the molecular bases of these disorders, therapy of MD is quite inadequate. Present options of treatment mainly include physical, pharmacological and gene therapy approaches. Aerobic exercise and physical therapy is useful to prevent or correct deconditioning and may improve exercise tolerance. Pharmacological approach is based on removing noxious metabolites, using reactive oxygen species scavengers and administrating vitamins and cofactors which is especially important in case of primary deficiencies of specific compounds such as Coenzyme Q10. Gene therapy is fascinating but it is difficult to apply because of polyplasmy and heteroplasmy. Experimental methods include gene shifting, allotopic expression, mitochondrial transfection or correcting mtDNA mutations with specific restriction endonucleases. Here, we discussed some recent patents. Progresses in each of these fields may open interesting perspectives for the future.

Binding a critical pentapeptide region on the scaffolding protein filamin A regulates signaling of mu opioid receptors so that their activation should not result in the opioid tolerance, dependence and addiction associated with current opioid painkillers. Additionally, we show that compounds that bind this site on filamin A reduce release of inflammatory cytokines. PTI-609 is a new chemical entity that binds filamin A with picomolar affinity and also activates opioid receptors via a novel binding domain. PTI-609 and analogs have similar analgesic efficacy to morphine by oral administration in mice, provide some anti-inflammatory activity in the rat collagen-induced arthritis model, and show no conditioned place preference at analgesic doses, suggesting no potential for abuse and addiction. PTI-609 was designed after discovering filamin A as the high-affinity target of naltrexone or naloxone. Combined with opiates, ultra-low-dose naloxone or naltrexone can enhance and prolong the analgesia of the opiate alone and prevent or attenuate opioid tolerance, dependence and addictive properties. We will review here the mechanism of action of ultra-low-dose naltrexone and naloxone, the discovery of filamin A as their high-affinity target, and the rationale as to why the current, dualfunction new chemical entity should not only be easier to develop but also more consistently efficacious than opioids combined with ultra-low-dose naltrexone. This new class of compounds, as well as the concept, screening assay and pharmacophore model, are covered in a family of recent patent applications.

Parkinson's disease is a neurodegenerative pathology which affects the dopaminergic neurons in the mesencephalon, leading to a progressive and relentless motor disability and to non-motor symptoms of different severity. The aim of this review is to summarize the features of drugs currently used in the pharmacotherapy of Parkinson's disease, with a look at their beneficial effects and limitations. Drugs acting on dopamine transmission, as L-DOPA, direct dopaminergic agonists, inhibitors for either the MAO or COMT enzymes and drugs acting on neurotransmitters other than dopamine (e.g. acetylcholine, glutamate) will be covered. Investigational drugs currently under examination for their therapeutic potential in Parkinson's disease and recent patents which may be relevant to the field will be also discussed.

It remains a challenge to deliver effective concentrations of therapeutics into CNS pathologies, which is primarily due to the fact that current and investigational CNS therapeutics are suboptimally-sized to accumulate to effective concentrations in individual diseased CNS tissue cells. The blood-CNS barrier of blood capillary microvasculature within neuropathologic tissues is known to be permeable to lipid-insoluble macromolecules in a widespectrum of neuropathologies. In the case of CNS solid tumor tissue blood capillaries, the physiological upper limit of pore size to the transcapillary passage of spherical lipid-insoluble macromolecules is approximately 12 nanometers, and systemically administered imageable dendrimer nanoparticles within the 7 to 10 nanometer size range accumulate to therapeutic concentrations in solid tumors since this size range of particles maintain peak blood concentrations for several hours. In preliminary pre-clinical studies, it has recently been shown that one intravenous dose of small molecule chemotherapy-conjugated imageable dendrimer nanoparticles within the 7 to 10 nanometer size range, with doxorubicin bound to the particle exterior via acid-labile covalent linkages, is effective at regressing orthotopic rodent malignant gliomas. Although it is foreseeable that such drug-conjugated imageable nanoparticles within the 7 to 10 nanometer size range will be effective theranostic agents for the concurrent treatment (i.e. neutron capture therapy) and imaging (i.e. magnetic resonance) of solid tumor disease, the issue of maintaining a neutralized particle exterior following the attachment of cationic drugs will need to be addressed to eliminate cationic charge-mediated nanoparticle toxicity to blood capillary walls. In this review, the ultrastructural basis for blood capillary microvascular permeability to lipid-insoluble macromolecules is discussed, and the importance of delineating the precise physiologic upper limits of pore size in the blood capillary microvasculature of other CNS pathologies, including neurodegenerative, inflammatory and ischemic CNS diseases, is emphasized. The discussion herein will serve as guide for the future development of optimally-sized, non-toxic and non-immunogenic lipid-insoluble systemic therapies, which should be the focus of future patent applications and patents on CNS drug development.

The advent of adult neurogenesis and neural stem cell (NSC) research opens new avenues and opportunities for treating neurological diseases and disorders, particularly for the discovery and development of novel drugs. Adult neurogenesis is modulated by a broad range of stimuli, physio- and pathological processes, trophic factors/cytokines and drugs, particularly drugs used for treating neurological diseases and disorders. Hence, adult neurogenesis is the target of drugs used for treating neurological diseases and disorders, such as Alzheimer's disease and depression, and the activities of neurological drugs may be mediated by adult NSCs. Although the contribution and mechanism of adult neurogenesis and newly generated neuronal cells of the adult brain in the activities of neurological drugs remain to be determined, new research is geared toward discovering and developing novel drugs that target specifically adult neurogenesis and the NSCs of the adult brain. Neurogenic drugs may reverse or compensate deficits and impairments associated with neurological diseases and disorders, particularly those associated with the hippocampus. They may have a potential for regenerative medicine and for the treatment of brain tumors. However, limitations in established models and protocols currently used in the drug discovery and development process of these drugs may hinder their potency and specificity. Here, we reviewed and discussed recent patents on neurogenic drugs and compounds, particularly nootropic agents and apigenin and related compounds.

The patents annotated in this section have been selected from various patent databases. These recent patents are relevant to the articles published in this journal issue, categorized by therapeutic areas/agent/targets and therapeutic agents related to CNS drug discovery.