Recent Patents on CNS Drug Discovery (Discontinued) - Volume 5, Issue 1, 2010

Transcranial Doppler ultrasonography (TCD) is the only non-invasive examination that provides a reliable evaluation of intracranial blood flow patterns in real-time, adding physiological information to the anatomical information obtained from other neuroimaging modalities. TCD is relatively cheap, can be performed bedside, and allows monitoring both in acute emergency settings as well as for prolonged periods with a high temporal resolution making it ideal for studying dynamic cerebrovascular responses. Extended applications of transcranial Doppler in enhancing intravenous thrombolysis in acute stroke, emboli monitoring, right-to-left shunt detection and vasomotor reactivity provide important information about the pathophysiology of cerebrovascular ischemia. In acute cerebral ischemia, TCD is capable of providing rapid information about the hemodynamic status of the cerebral circulation, monitoring recanalization in realtime with a potential for enhancing tissue plasminogen activator (TPA) induced thrombolysis. Advanced applications of TCD make it an important and valuable tool for evaluating stroke mechanisms, plan and monitor treatment and determine prognosis. TCD has an established clinical value in the diagnostic workup of stroke patients and is suggested as essential components of a comprehensive stroke center. We have reviewed various recent patents in addition to the diagnostic, therapeutic, as well as, prognostic applications of TCD in patients with cerebrovascular disease.

Voltage-gated calcium channels are one of the major ion channels distributed in the human central nervous system, and mediate an influx of extracellular Ca2+ in response to membrane depolarization. Calcium channels are of particular interest in a broad range of cellular functions including cell proliferation and differentiation, gene expression, neurite outgrowth, transmitter and hormone release, and brain plasticity. The dysfunction of calcium channels is related to a variety of clinical disorders such as migraine, hemiplegia, and epilepsy. Therefore, calcium channels have gained great pharmaceutical interest as a privileged target class for the treatment of a wide range of human diseases. This review will examine the known marketed peptide drugs for calcium channels and address the development of some important patented peptide molecules targeting calcium channels.

The glutamate hypothesis of schizophrenia suggests that hypofunction of N-methyl-D-aspartate (NMDA) receptors may be critical for schizophrenic symptoms; therefore, pharmacological approaches that enhance NMDA function may be beneficial for the treatment of schizophrenia. Several lines of evidence indicate that NMDA and metabotropic glutamate (mGlu) 5 receptors are closely associated signaling partners and that a selective mGlu5 receptor agonist might provide a viable approach for increasing NMDA receptor function in the treatment of schizophrenia. The orthosteric binding sites across members of the mGlu receptor subtype for a particular endogenous ligand are often highly conserved, making it difficult to achieve high selectivity for the specific mGlu5 receptor. The advanced currents of drug discovery have developed multiple highly selective allosteric modulators of mGlu5 receptor. In the present review, we provide an update of the recent patents and development of positive allosteric modulators of the mGlu5 receptor and explore their therapeutic potential for schizophrenia.

Inflammation arises in the CNS from a number of neurodegenerative and oncogenic disorders, as well as from ischemic and traumatic brain injuries. These pathologies give rise to increased levels of extracellular adenine nucleotides which, via activation of a variety of cell surface P2 purinergic receptors, influence the inflammatory activities of responding immune cells. One P2 receptor subtype in particular, the P2X7 receptor, potentiates the release of proinflammatory cytokines, such as interleukin-1β (IL-1β) from macrophage-like cells. It is also thought to contribute to secondary brain injury by inducing neuronal cell death. Therefore, antagonism of this receptor could have significant therapeutic impact on all disorders, not just CNS, to which excessive inflammatory activities contribute. The use of currently available P2X7 receptor antagonists for the treatment of CNS inflammation has been limited to the generally non-selective antagonists PPADS, oxidized ATP, Brilliant Blue G, suramin, calmidizolium, and KN-62. However, the recent patents and development of novel P2X7 receptor antagonists, as discussed in this review, will provide new tools both for clinical and research purposes. Here we discuss compounds for which patents have been applied since 2006, from the following categories: benzamide inhibitors, bicycloheteroaryl compounds, acylhdranzine antagonists, biaromatic P2X7 antagonists, heterocyclic compounds and amide derivatives, and aromatic amine antagonists.

For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Δ9- tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex®) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article reviews recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.

Despite the intensive recent research in cancer therapy, the prognosis in patients affected by high-grade gliomas is still very unfavorable. The efficacy of classical anti-cancer strategies is seriously limited by lack of specific therapies against malignant cells. The extracellular matrix plays a pivotal role in processes such as differentiation, apoptosis, and migration in both the normal and the pathologic nervous system. Glial tumors seem to be able to create a favorable environment for the invasion of glioma cells in cerebral parenchyma when they combine with the extracellular matrix via cell surface receptors. Glioma cells synthesize matrix proteins, such as tenascin, laminin, fibronectin that facilitate the tumor cell's motility. New treatments have shown to hit the acting molecules in the tumor growth and to increase the efficacy and minimize the toxicity. Antisense oligonucleotides are synthetic stretches of DNA which hybridize with specific mRNA strands. The specificity of hybridization makes antisense method an interesting strategy to selectively modulate the expression of genes involved in tumorigenesis. In this review we will focus on the mechanisms of action of antisense oligonucleotides and report clinical and experimental studies on the treatment of high-grade gliomas. We will also report the patents of preclinical and/or clinical studies that adopt the antisense oligonucleotide therapy list in cerebral gliomas.

For decades, the struggle against inflammation and related disorders has constituted an important field in medical practice, with strategies mainly aimed to inhibit the compounds produced through the arachidonic acid pathway. Thus, specific COX-2 inhibitors or “coxibs”, have been recently designed that play an important but controversial role in reducing inflammatory phenomenon. Lately, several patents have been generated which target the specific inhibition of microsomal Prostaglandin E synthase-1 (mPGES-1). This enzyme, which was cloned and characterized at the end of nineties, catalyzes under inflammatory stimuli the last step of PGE2 synthesis. A corpus of data is now available, illustrating the pivotal role played by this enzyme in numerous symptoms linked to inflammation such as fever, anorexia or pain. The present review highlights the current state of knowledge of the involvement of mPGES-1 in sickness behaviour and in other inflammation-related disorders and summarizes the recent patents related to mPGES-1 and its specific inhibition.

Drug addiction and alcoholism are behavioural disorders characterized by a profound alteration of several brain circuits induced by chronic drug use. Their treatment is yet based on empiricism and today only few pharmacological strategies are fully effective to control both drug use and relapse. The present paper reviews the most updated pharmacotherapies able to contrast both alcoholism and drug addiction including the new patented drugs and the future therapeutic trends.

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