Recent Patents on CNS Drug Discovery (Discontinued) - Volume 2, Issue 3, 2007

Injured axons in the adult central nervous system (CNS) exhibit almost no regeneration. Several myelin-associated proteins such as myelin-associated glycoprotein (MAG), Nogo, and oligodendrocyte-myelin glycoprotein (OMgp) have been identified as inhibitors of CNS axonal regeneration in the CNS. Recently, repulsive guidance molecule (RGM) was identified as a potential myelinderived neurite outgrowth inhibitor in vitro and in vivo. These axonal growth inhibitors transmit inhibitory signals through common intracellular molecules such as RhoA and its effector Rho kinases (ROCK). The effects of these axonal growth inhibitors are blocked by inhibition of the Rho-ROCK pathway in vitro. Injuries to the adult CNS induce the activation of the Rho-ROCK pathway, and the inhibition of this pathway promotes axonal regeneration and functional recovery in the injured CNS. Therefore, the Rho-ROCK pathway is a promising target for drug development for the treatment of human CNS injuries such as spinal cord injuries. This review also discusses recent patents and future developments which are useful in the treatment of human CNS injuries.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by deposition of extracellular amyloid plaques, formation of intracellular neurofibrillary tangles and neuronal dysfunction in the brain. A growing body of evidence indicates a central role for biometals such as copper in many critical aspects of AD. The amyloid beta (Aβ) peptide and its parental molecule, the amyloid precursor protein (APP) both modulate Cu and Zn metabolism in the brain. Therefore, aberrant changes to APP or Aβ metabolism could potentially alter biometal homoestasis in AD, leading to increased free radical production and neuronal oxidative stress. Modulation of metal bioavailability in the brain has been proposed as a potential therapeutic strategy for treatment of AD patients. The lipid permeable metal complexing agent, clioquinol (CQ), has shown promising results in animal models of AD and in small clinical trials involving AD patients. Moreover, a new generation of metal-ligand based therapeutics is currently under development. Patents now cover the generation of novel metal ligand structures designed to modulate metal binding to Aβ and quench metal-mediated free radical generation. However, the mechanism by which CQ and other metal complexing agents slows cognitive decline in AD animal models and patients is unknown. Increasing evidence suggests that ligand-mediated redistribution of metals at a cellular level in the brain may be important. Further research will be necessary to fully understand the complex pathways associated with efficacious metal-based pharmaceuticals for treatment of AD.

Accumulation of Aβ peptide in the brain results in the formation of amyloid plaques characteristic of Alzheimer's disease (AD) pathology. Aβ soluble oligomers and protofibrils are neurotoxic and these are believed to be a major cause of neurodegeneration in AD. Aβ is derived from a precursor protein by two sequential cleavage steps involving β- and γ-secretases, two proteolytic enzymes that represent rational drug targets. β-secretase was identified as the membrane-anchored aspartyl protease BACE (or BACE1) and found to be elevated in brain cortex of patients with sporadic Alzheimer's disease. In this review, we summarize current approaches towards the development of BACE inhibitors with focus on bioactive compounds and related patents. Recent reports have described drugs that are effective at inhibiting Aβ production in the brain of transgenic mouse models. The beginning of Phase I clinical trials has been approved for one of them and we can expect that in the near future BACE inhibitors will provide novel effective therapeutics to treat AD.

Potassium (K+) channels are the most heterogeneous and widely distributed class of ion channels. K+ channels are dynamic pore-forming transmembrane proteins known to play important roles in all cell types underlying both normal and pathophysiological functions. Essential for such diverse physiological processes as nerve impulse propagation, muscle contraction, cellular activation and the secretion of biologically active molecules, various K+ channels are recognized as potential therapeutic targets in the treatment of multiple sclerosis, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, brain tumors, brain/spinal cord ischemia, pain and schizophrenia, migraine, as well as cardiac arrhythmias, pulmonary hypertension, diabetes, cervical cancer, urological diseases and sepsis. In addition to their importance as therapeutic targets, certain K+ channels are gaining attention for their beneficial roles in anesthesia, neuroprotection and cardioprotection. The K+ channel gene families (subdividing into multiple subfamilies) include voltage-gated (Kv: Kv1-Kv12 or KCNA-KCND, KCNF-KCNH, KCNQ, KCNS), calcium-activated (KCa: KCa1-KCa5 or KCNM-KCNN), inwardly rectifying (Kir: Kir1- Kir7 or KCNJ) and background/leak or tandem 2-pore (K2P: K2P1-K2P7, K2P9-K2P10, K2P12-K2P13, K2P15-K2P18 or KCNK) K+ channels. Worldwide, the pharmaceutical industry is actively developing better strategies for targeting ion channels, in general, and K+ channels, in particular, already generating over $6 billion in sales per annum from drugs designed to block or modulate ion channel function. This review provides an overview of recent patents on emerging K+ channel blockers and activators (openers) with potential for development as new and improved nervous system therapeutic agents.

In the last decade, current opinion for Parkinson disease (PD) etiology has swung from the hypothesis of a toxic/environmental disorder to understanding it as a highly heritable condition. Recent research conducted in families affected from PD has disclosed 6 genes that codify for proteins in pathways of neurodegeneration in PD. This review focuses in new drugs aimed to prevent the apparition and progression of the disease developed after the knowledge obtained from the genetic studies of PD, covering most recent and important patents.

Obesity is considered one of the risk factors for metabolic disorders. There is increasing evidence that obesity is under control of several cytokines and hormone in the brain. Brain histamine and H3 receptors are important factors for regulating obesity. The results of physiological and pharmacological studies revealed that brain histamine and H3 receptors are involved in the regulation of obesity. In this review, we describe the implication and patent for developing H3 receptor antagonists and their therapeutic potential of obesity.

Melatonin, the pineal gland hormone, is widely distributed in mammalian tissues and exerts its action via two melatonin receptor sub-types, MT1 and MT2. Melatonin is known to play functional roles in regulating circadian rhythms and seasonal reproduction. In recent years, growing evidence has also linked melatonin to a variety of other body systems and disease states, thus highlighting its significance as a therapeutic agent. However, due to its properties, melatonin is ineffective in clinical use, thus prompting the development of melatoninergic ligands that mimic the actions of melatonin but in a manner that is more potent and specific for melatonin receptors. An additional focus has been to develop ligands that exhibit receptor subtype selectivity. While there are over seventy patents on melatoninergic ligands, success in developing therapeutically effective melatoninergic ligands have been varied. However, the recent approval of Ramelteon for treatment of sleep disorders and the evaluation of other compounds in clinical trials have highlighted their clinical importance. In this review an overview of recently developed novel melatoninergic ligands is provided including recently filed patents and compounds undergoing clinical evaluation.

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