Recent Patents on CNS Drug Discovery (Discontinued) - Volume 6, Issue 2, 2011

Huntington's disease (HD) is an autosomal dominant inherited and progressive neurodegenerative disorder with motor dysfunction and cognitive deficits. Although, there are no treatments to delay the appearance and the progression of HD, there are potential drugs currently in preclinical and clinical trials that are focused on HD therapy. The signaling pathways involved in HD are not yet clearly elucidated; however, expression of mutant huntingtin protein is considered a key factor in the induction and/or progression of HD. The demonstration that the onset and progression of HD in models of transgenic mice, in particular, are delayed or improved by the application of neurotrophic factors has emphasized their importance in neuroprotection in HD. In addition, other compounds targeting the HD gene or mutant huntingtin protein are currently in preclinical and clinical testing and may show promising neuroprotective effects. There are current patented drugs that are currently being considered as potential therapeutics for HD. These patented drugs may provide promising therapy for HD.

Current drug development for the treatment of Alzheimer's disease is principally based on the amyloid cascade theory, and aims to reduce the levels of Aβ amyloid peptide in the brain. This can be achieved, either by decreasing peptide production through inhibition of β-secretase (also known as BACE-1) or γ-secretase, or by interfering with Aβ aggregation, or by promoting Aβ clearance. Targeting BACE-1, the proteolytic enzyme that initiates Aβ formation, has generated a lot of research interest recently and is currently thought to be one of the most promising therapeutic approaches. In this review, we summarize and discuss the latest patents and publications describing BACE-1 inhibitors, principally focussing on their drug properties and performance in preclinical trials.

The blood-brain barrier (BBB) is a regulatory interface between the circulation and the central nervous system (CNS). Therapy of neurological diseases is limited due to restricted penetration of pharmacons across the BBB. Models for screening the brain penetration of drug candidates are needed early in drug discovery. Culture-based models are useful tools for both basic research on BBB, and testing the permeability of new therapeutical molecules. This review focuses on patented in vitro BBB models and their potential application in CNS drug discovery. Cell culture models using primary and immortalized brain endothelial cells of non-human and human origin, in co-culture or mono-culture setting, in static or dynamic conditions are discussed, as well as methods to induce BBB properties in such in vitro models. The aim of these models is to reproduce as many aspects as possible of the in vivo BBB. All models should show some elements of general endothelial and specific BBB properties, like physiologically realistic cell architecture, restrictive paracellular pathway, and functional expression of transport mechanisms. Though no “ideal in vitro BBB model” has been constructed yet, the currently available models provide valuable information on BBB permeability and are useful tools in CNS drug discovery.

The role of muscarinic and nicotinic cholinergic receptors in analgesia and neuropathic pain relief is relatively unknown. This review describes how such drugs induce analgesia or alleviate neuropathic pain by acting on the central cholinergic system. Several pharmacological strategies are discussed which increase synthesis and release of acetylcholine (ACh) from cholinergic neurons. The effects of their acute and chronic administration are described. The pharmacological strategies which facilitate the physiological functions of the cholinergic system without altering the normal modulation of cholinergic signals are highlighted. It is proposed that full agonists of muscarinic or nicotinic receptors should be avoided. Their activation is too intense and un-physiological because neuronal signals are distorted when these receptors are constantly activated. Good results can be achieved by using agents that are able to a) increase ACh synthesis, b) partially inhibit cholinesterase activity c) selectively block the autoreceptor or heteroreceptor feedback mechanisms. Activation of M1 subtype muscarinic receptors induces analgesia. Chronic stimulation of nicotinic (N1) receptors has neuronal protective effects. Recent experimental results indicate a relationship between repeated cholinergic stimulation and neurotrophic activation of the glial derived neurotrophic factor (GDNF) family. At least 9 patents covering novel chemicals for cholinergic system modulation and pain control are discussed.

Metoclopramide is a well-known anti-emetic drug with central and peripheral pharmacological effects. Some authors have reported metoclopramide as an adjunct therapy to other analgesics in patients with migraine attacks. Treatment of migraine headache using a mix of metoclopramide and an NSAID has been patented (European Patent EP1014961) as well as a short series showing great efficacy and tolerability of metoclopramide in patients wtih migraine attacks. We decided to conduct an open, single-blind, parallel control study in the emergency department to evaluate the efficacy and tolerability of metoclopramide in patients with severe migraine attacks. 93 consecutive patients with severe migraine attacks were randomized into two groups (groups A and B). Patients in group A received 10mg of intravenous metoclopramide and patients in group B received 1 g of intravenous paracetamol. Patients were evaluated 5minutes before (baseline), 15, 30, 60 and 120 minutes after drug delivery, and before being discharged from the emergency department They were then contacted by phone 48 hours after being discharged from the hospital (phone questionnaire). Patients treated with either metoclopramide or paracetamol showed a significant reduction in the intensity of pain at the 120 minute time point, with an 86% and 82% improvement respectively. However, patients treated with metoclopramide showed a more rapid improvement at the 15 and 30 minute evaluations. Patients with severe migraine attacks treated with metoclopramide as monotherapy showed a significant improvement in terms of pain relief and a faster improvement in pain intensity compared to those treated with paracetamol. Metoclopramide and other dopamine antagonistic drugs should be considered a therapeutic option in severe migraine headache attacks

Cocaine dependence is characterized by compulsive drug seeking and high vulnerability to relapse. Overall, cocaine remains one of the most used illicit drugs in the world. Given the difficulty of achieving sustained recovery, pharmacotherapy of cocaine addiction remains one of the most important clinical challenges. Recent advances in neurobiology, brain imaging and clinical trials suggest that certain medications show promise in the treatment of cocaine addiction. The pharmacotherapeutic approaches for cocaine dependence include medications able to target specific subtypes of dopamine receptors, affect different neurotransmitter systems (i.e. noradrenergic, serotonergic, cholinergic, glutamatergic, GABAergic and opioidergic pathways), and modulate neurological processes. The systematic reviews concerning the pharmacological treatment of cocaine dependence appear to indicate controversial findings and inconclusive results. The aim of future studies should be to identify the effective medications matching the specific needs of patients with specific characteristics, abandoning the strategies extended to the entire population of cocaine dependent patients. In the present review we summarize the current pharmacotherapeutic approaches to the treatment of cocaine dependence with a focus on the new patents.

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.