Recent Patents on CNS Drug Discovery (Discontinued) - Volume 6, Issue 3, 2011

Obesity is one of the most important and disturbing global epidemic that affects humans, with more than 2 billion people overweight and 700 million obese predicted for 2015 by the World Health Organization. Obesity treatment represents then one of the most exciting challenges for the academic researchers and the pharmaceutical industry. But to date, this community failed to develop safe and effective treatments with a good risk/benefit profile. Indeed, most of the drugs previously used as anti-obesity agents have been withdrawn from the market for safety issues, and therapeutic options in form of a medication are currently very limited. This last decade however, new advances in our understanding of central pathways controlling food intake, body weight and energy homeostasis have led to the discovery of new molecular targets that could provide interesting options in the fight against obesity. This review aims to be an overview of the new patents exploiting the anorexigenic properties of the central catabolic pathways or aimed at blocking the orexigenic effects of the anabolic pathways, in the hope to develop new anti-obesity drugs.

Ultrasonography provides a unique diagnostic perspective in cerebrovascular disorders, with extremely high temporal resolution and excellent spatial display of extracranial as well as intracranial arteries. Unlike other imaging modalities, cerebrovascular ultrasound provides real-time information about the blood flow in addition to the hemodynamic changes as a result of various physiological as well as pathological states. The information obtained from cerebrovascular ultrasound has diagnostic, therapeutic as well as prognostic value in various disease states. 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. Cerebrovascular ultrasonography 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. Extended applications of TCD provide important information about the pathophysiology of cerebrovascular ischemia. Advanced applications of cerebrovascular ultrasonography have become an integral part of the armamentarium of stroke neurologists for evaluating stroke mechanisms, plan and monitor treatment and determine prognosis. It has been suggested as an essential component of a comprehensive stroke center. We have reviewed various recent patents in addition to the established applications of cerebrovascular ultrasonography in patient selection for various stroke interventions.

The brain controls coping with aversive situations, modulating the activity of the adaptive systems (the nervous, endocrine and immune systems). In this review, we focus the involvement of the hypothalamus-pituitary-adrenal (HPA) axis in the stress response. In the physiological response, the hypothalamic paraventricular nucleus secretes CRH (corticotrophin releasing hormone) that stimulates pituitary ACTH (adrenocorticotropic hormone), through CRH-receptor type 1 (CRH-R1). In turn, ACTH activates adrenal glands to produce cortisol, acting on type-2 melanocortin receptors (MC2-R). The glucocorticoid negative feedback inhibits the HPA axis activity through the glucocorticoid receptor (GR). The hippocampus plays a central role as an important connection between cortex and hypothalamus, and, together with the suprachiasmatic nucleus (SCN), regulates cortisol rhythm. Peripherally, an important regulator of cortisol metabolism in local tissues is 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), that produces cortisol within the splanchnic bed. The stress response during chronic conditions increases vulnerability to diseases through the activation of adaptive systems, in particular, the HPA axis. Increased levels of allostatic load (a measure of stress with multisystem dysregulation) are associated with the development of functional and cognitive decline, frailty and with mortality in high-functioning older adults. Moreover, HPA axis hyperactivity is a feature that can be present in chronic diseases, affecting endocrine (abdominal obesity, type-2 diabetes mellitus), cardiovascular (atherosclerosis, essential hypertension) and nervous system (dementia, depression), particularly during comorbid conditions. In conclusion, the spectrum of molecules interacting at the different levels of HPA axis is exponentially increasing, ranging from supra-hypothalamic targets to post-receptor mechanisms and it includes agents acting on SCN, CRH-R1 receptor, adrenal steroidogenesis, GR and peripheral/central 11β-HSD1 enzyme. This area of research is rapidly advancing in order to develop therapeutic strategies to counteract HPA axis hyperactivity and to reduce the burden of stress-related disorders. The article presented some promising patents on the strategies against glucocorticoid-mediated brain damage.

Ejaculation is a complex and still poorly understood neurological mechanism, at both spinal and cerebral levels as it is closely associated with orgasm. Physiologically, ejaculation is defined as the expulsion of seminal fluid from the urethral meatus and consists of two phases, namely emission and expulsion. Ejaculation is mediated by a spinal control center, referred to as a spinal pattern generator that coordinates sympathetic, parasympathetic and motor (somatic) outflows, integrating the latter with the inputs from the supraspinal sites in brainstem, hypothalamus and preoptic area. Premature ejaculation (PE) is the most common sexual dysfunction among young men, and it has been considered mostly psychogenic in origin, although it can be associated to diverse urological and neurological diseases. On the contrary, retrograde ejaculation and anejaculation are predominantly related to organic causes, particularly to neurogenic ones. Since ejaculation is mostly a spinal reflex, it is comprehensible that ejaculatory disorders are more frequent in spinal cord injury than in other neurological disorders. Over the past decades, research has focused on PE, and evidence from clinical studies showed a beneficial effect of antidepressants for the treatment of men with PE. Other ejaculatory disorders, especially painful ejaculation, have been less investigated and the proper therapy is still controversial. Aim of this review is to provide a comprehensive description of both currently available treatments and most promising future therapies, including assigned patents, for the neurogenic ejaculatory disorders.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuropathological features comprising amyloid deposits and neuronal losses in brain. In AD, aggregation of a β-amyloid peptide (Aβ), produced from proteolytic cleavage of amyloid precursor protein, is believed to be implicated in the pathophysiological cascade leading to neuronal death. Most AD drugs currently available can only alleviate symptoms rather than modify the underlying molecular cause of AD. In this review, we describe and discuss the recent patents issued within the past two years focusing on therapeutic interventions targeting at various Aβ-associated pathological mechanisms of AD. The described therapeutic strategies include 1) reduction of synthesis of Aβ, 2) inhibition of Aβ aggregation, 3) immunotherapeutic/enzymatic clearance of Aβ, 4) targeting other amyloidogenic proteins interacting with Aβ and 5) amelioration of Aβ downstream toxic effects. Important issues to be considered for further improvement of therapeutic efficacy of these approaches are also discussed.

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....