Histamine H4 receptor ligands and their potential therapeutic applications: an update

Introduction: Several studies underlined the critical role of histamine H4 receptor (H4R) in inflammation, thus H4 modulators have been suggested as promising drug candidates in inflammatory diseases. First H4 ligands typically have indole or amino-pyrimidine scaffolds. During the last few years, however, serious efforts have been made to identify novel H4 chemotypes with improved pharmacodynamic and pharmacokinetic properties.

Areas covered: Areas covered in this review include an overview on H4 ligands published in scientific papers, as well as in patent applications between 2009 and 2011. Recently discovered scaffolds possessing significant H4 activity were analyzed and their therapeutic potential was reviewed.

Expert opinion: Recent results from the scientific literature and novel patent applications reinforce the major role of H4R in inflammatory diseases such as pruritus, asthma, inflammatory pain and allergic rhinitis. Novel studies suggest further indications of H4 modulators in cancer, neuropathic pain, vestibular disorders and type 2 diabetes. The number of active H4 chemotypes was increased significantly. The first H4 antagonist entered to clinics and the results from a proof-of-concept Phase II clinical study is expected to be disclosed soon.     

Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders

ABSTRACT

Introduction: Adverse immune activation contributes to many central nervous system (CNS) disorders. All main CNS cell types express toll-like receptor 4 (TLR 4). This receptor is critical for a myriad of immune functions such as cytokine secretion and phagocytic activity of microglia; however, imbalances in TLR 4 activation can contribute to the progression of neurodegenerative diseases.

Areas covered: We considered available evidence implicating TLR 4 activation in the following CNS pathologies: Alzheimer’s disease, Parkinson’s disease, ischemic stroke, traumatic brain injury, multiple sclerosis, multiple systems atrophy, and Huntington’s disease. We reviewed studies reporting effects of TLR 4-specific antagonists and agonists in models of peripheral and CNS diseases from the perspective of possible future use of TLR 4 ligands in CNS disorders.

Expert opinion: TLR 4-specific antagonists could suppress neuroinflammation by reducing overproduction of inflammatory mediators; however, they may interfere with protein clearance mechanisms and myelination. Agonists that specifically activate myeloid differentiation primary-response protein 88 (MyD88)-independent pathway of TLR 4 signaling could facilitate beneficial glial phagocytic activity with limited activity as inducers of proinflammatory mediators. Deciphering the disease stage-specific involvement of TLR 4 in CNS pathologies is crucial for the future clinical development of TLR 4 agonists and antagonists.     

5-HT7 receptor modulators: a medicinal chemistry survey of recent patent literature (2004 – 2009)

Importance of the field: The 5-HT₇ receptors are discretely localized within the CNS (thalamus, hypothalamus, limbic and cortical regions). The 5-HT₇ receptors are also present in smooth muscle cells from blood vessels and have been reported in gastrointestinal tract as well as in rat lumbar dorsal root and sympathetic ganglia. The 5-HT₇ receptors have been implicated in depression, disorders related to circadian rhythms, pain and migraine. Thus, there is a great interest in developing potent and selective 5-HT₇ receptor modulators.

Areas covered in this review: This review article highlights the research advances published in the patent literature between January 2004 and December 2009, giving emphasis to the medicinal chemist's standpoint.

What the reader will gain: Readers will rapidly gain an overview of the various 5-HT₇ receptor modulators reported in the patent literature in the past 6 years. Furthermore, the readers will learn which structure type can interact with 5-HT₇ receptor and also the different companies that are the main players in the field.

Take home message: Although no 5-HT₇ modulator has entered clinical trials, the development and future use of different agonists and antagonists suitable for use in vivo seem very promising.     

Novel GABAB receptor positive modulators: a patent survey

Importance of the field: Positive allosteric modulators of GABA_B receptors may have a similar potential as positive modulators of GABA_A receptors, the benzodiazepines discovered in 1957. The discovery of positive allosteric modulators of GABA_B receptors at Novartis in Basel in 2000 opened the way to search for compounds, which activate GABA_B receptors without the drawbacks of full agonists, such as desensitization, tolerance, muscle-relaxant effects, hypothermia, and central and gastrointestinal side effects.

Areas covered in this review: Numerous animal experiments point out that several indications can be addressed with positive modulators of GABA_B receptors, such as depression, anxiety, schizophrenia, neuropathic and chronic pain and treatment of craving for drugs of abuse, such as alcohol, cocaine and nicotine. Peripherally acting compounds may be valuable drugs for the treatment of gastroesophageal reflux disease and irritable bowel syndrome.

What the reader will gain: An overview on 19 patents in this field, of the different scaffolds for positive modulators of GABA_B receptors and of the major players in the field.

Take home message: The search for subtype selective benzodiazepine receptor ligands has proved to be extremely difficult. Positive modulators of GABA_B receptors may provide novel anxiolytic drugs faster.     

Novel prostaglandin receptor modulators: a patent review (2002 – 2012) – part I: non-EP receptor modulators

Introduction: Prostaglandins and their G-protein coupled receptors play numerous physiological and pathophysiological roles especially in inflammation and its resolution. The variety of physiological effects mediated by prostanoids makes prostanoid receptors valuable drug targets and the research on prostaglandin receptor modulators is intensive. Prostaglandin receptor targeting drugs might be beneficial for the treatment of inflammatory, allergic, respiratory and cardiovascular disorders as well as treatment of pain but several novel fields of use such as cancer and ophthalmic diseases have also been found apart from these classical indications.

Areas covered: Evaluation of the patent activity over the last decade (2002 – 2012) illustrates many potent and selective modulators of the distinct prostanoid receptors and some novel methods for their use besides the classical indications. By now, some prostaglandin receptor antagonists already have reached clinical development.

Expert opinion: Though the structural diversity of compounds targeting prostanoid receptors is not really large, several highly potent agents with favorable properties have been developed. The clinical potential of FP, IP, TP and DP modulators remains to be investigated, while first very promising clinical results are available as far as CRTH2 is concerned.     

The design and discovery of T-type calcium channel inhibitors for the treatment of central nervous system disorders

Introduction: Neuronal T-type calcium channels (T-type channels) are expressed throughout the central nervous system (CNS), regulating neuronal excitability. T-type channels in the CNS are involved in various neurophysiological and pathophysiological states, and thus have become a promising therapeutic target.

Areas covered: This article discusses T-type channel-related CNS disorders such as epilepsy, neuropathic pain, insomnia and tremor disorders including Parkinson's disease. In addition, the article reviews T-type channel inhibitors showing efficacy in animal models in such CNS disorders, with a focus on classical T-type channel inhibitors with limited specificity for T-type channels as well as novel inhibitors with high specificity. Furthermore, the article also presents and discusses the next generation of T-type channel inhibitor discovery, virtual as well as screening and high-throughput screening techniques.

Expert opinion: Although T-type channel-related CNS disorders seem to be diverse, it converges into the one major cause – abnormal hyperactivity of neurons. T-type channel-specific inhibitors could thus be commonly applied for the treatment of such CNS disorders regardless of the complexity of individual disorder. Structural information of inhibitor-binding sites would facilitate the discovery of the next generation of T-type channel-specific inhibitors by stimulating structure-based rational drug designs.     

MDV3100 for the treatment of prostate cancer

Introduction: Current methods for treating prolonged and neuropathic pain are inadequate and lead to toxicities that greatly diminish quality of life. Therefore, new approaches to the treatment of pain states are needed to address these problems.

Areas covered: The review primarily reviews approaches that have been taken in the peer-reviewed literature of multivalent ligands that interact with both μ and δ opioid receptors as agonists, and in some cases, also with pharmacophores for antagonist ligands that interact with other receptors as antagonists to block pain.

Expert opinion: Although there are a number of drugs currently on the market for the treatment of pain; none of them are 100% successful. In the authors' opinion, it is clear that new directions and modalities are needed to better address the treatment of prolonged and neuropathic pain; one drug or class clearly is not the answer for all pain therapy. Undoubtedly, there are many different phenotypes of prolonged and neuropathic pain and this should be one avenue to further develop appropriate therapies.     

Solid lipid nanoparticles as a drug delivery system for the treatment of neurodegenerative diseases

ABSTRACT

Introduction: The failure of many molecules as CNS bioactive compounds is due to many restrictions: poor water solubility, intestinal absorption, in vivo stability, bioavailability, therapeutic effectiveness, side effects, plasma fluctuations, and difficulty crossing physiological barriers, like the brain blood barrier (BBB), to deliver the drug directly to the site of action.

Area covered: Nanotechnology-based approaches with the employment of liposomes, micelles, dendrimers, and solid lipid nanoparticles (SLN) as drug delivery systems, are used to overcome the above reported limitations. Here, we focus on the delivery of drugs based on SLN formulation to treat neurodegenerative diseases. Notably, SLN have the ability to protect drugs from chemical and enzymatic degradation, direct the active compound towards the target site with a substantial reduction of toxicity for the adjacent tissues, and pass physiological barriers increasing bioavailability without resorting to high dosage forms.

Expert opinion: We believe that SLN could represent a suitable tool to pass the BBB and permit drugs to reach damaged areas of the CNS in patients affected by neurodegenerative pathologies, such as Alzheimer’s and Parkinson’s diseases.     

An overview of investigational antiapoptotic drugs with potential application for the treatment of neurodegenerative disorders

Importance of the field: The increase in life expectancy in developed countries has given rise to several emerging social problems. Of particular note is the dramatic rise in the incidence of neurodegenerative diseases. Given this new social scenario, there is a need to identify therapeutic strategies to delay the advance of these pathologies, for which no effective treatment is currently available.

Areas covered in this review: The present review discusses some of the drugs that are now under development with antiapoptotic activity or currently on the market that may have a potential application for the treatment of neurodegenerative diseases. Moreover, we also comment on potential compounds such as resveratrol and melatonin. Despite the lack of information from clinical trials on these two compounds, they are attracting considerable attention because of their natural origin and antioxidant and antiapoptotic action. Furthermore, they do not show toxicity in humans. In addition, we discuss the potential application of several compounds, such as NMDA antagonists, JNK inhibitors and GSK-3 inhibitors, for the treatment of neurodegenerative disorders.

What the reader will gain: This article will review recent developments in the field of apoptosis inhibitors, which might provide future tools for the treatment of the neurodegenerative diseases.

Take home message: The treatment of neurodegenerative diseases is a major challenge in medicine. This is partly because the incidence of these disorders is expected to rise in the coming years. New developments in the field of apoptosis inhibitors may provide future tools for the treatment of the aforementioned neurodegenerative diseases.     

Bicyclic bis-heteroaryl derivatives as inhibitors of the α-synuclein protein: a patent evaluation of WO2018138088A1

ABSTRACT

Introduction: Neurodegenerative diseases commonly present misfolding and aggregation of one or more proteins, including α-synuclein, β-amyloid, and tau. Several research efforts have been made to develop therapeutic agents able to reduce the neurotoxic effects of aggregated proteins. Among these, inhibition of α-synuclein by small molecules has been considered as a promising approach.

Areas covered: Bis-heteroaryl derivatives based on the N‐[1‐(1H‐indol‐3‐yl)hexan‐2‐yl]‐1,3‐thiazole‐5‐carboxamide scaffold with different heterocyclic substitutions at the 2-thiazole position showed interesting ability to inhibit self-aggregation of α-synuclein in vitro and were claimed as potential therapeutics for various neurodegenerative diseases. The potential of the presented compounds is evaluated with respect to other similar small molecule modulators of protein aggregation reported in the patent literature.

Expert opinion: The compounds presented with ability to inhibit aggregation of α-synuclein in vitro in the low micromolar range. The biggest drawback of the presented application is the absence of pharmacokinetic, toxicity, and in vivo efficacy data. On the other hand, the number of applications in this area by UCB Biopharma SPRL (four published in last 2 years) and promising pharmacokinetic and in vivo data disclosed in a previous patent on similar molecules, indicate that these compounds may hold value as therapeutic agents for neurodegenerative disorders.     

Sigma-1 receptors and animal studies centered on pain and analgesia

Introduction: Neuropathic pain is difficult to relieve with standard analgesics and tends to be resistant to opioid therapy. Sigma-1 receptors activated during neuropathic injury may sustain pain. Neuropathic injury activates sigma-1 receptors, which results in activation of various kinases, modulates the activity of multiple ion channels, ligand activated ion channels and voltage-gated ion channels; alters monoamine neurotransmission and dampens opioid receptors G-protein activation. Activation of sigma-1 receptors tonically inhibits opioid receptor G-protein activation and thus dampens analgesic responses. Therefore, sigma-1 receptor antagonists are potential analgesics for neuropathic and adjuvants to opioid therapy.

Areas covered: This article reviews the importance of sigma-1 receptors as pain generators in multiple animal models in order to illustrate both the importance of these unique receptors in pathologic pain and the potential benefits to sigma-1 receptor antagonists as analgesics.

Expert opinion: Sigma-1 receptor antagonists have a great potential as analgesics for acute neuropathic injury (herpes zoster, acute postoperative pain and chemotherapy induced neuropathy) and may, as an additional benefit, prevent the development of chronic neuropathic pain. Antagonists are potentially effective as adjuvants to opioid therapy when used early to prevent analgesic tolerance. Drug development is complicated by the complexity of sigma-1 receptor pharmacodynamics and its multiple targets, the lack of a specific sigma-1 receptor antagonist, and potential side effects due to on-target toxicities (cognitive impairment, depression).     

5-HT2C receptor modulators: a patent survey

Importance of the field: The 5-HT_2C receptor is a GPCR and is one of the 14 subtypes that constitute the serotonin receptor family. The 5-HT_2C receptor is exclusively expressed in the CNS where it demonstrates a wide distribution and displays high-affinity interactions with a wide variety of psychiatric medications. Modulators of 5-HT_2C have been implicated as a potential treatment for diseases of significant unmet medical need, including obesity, schizophrenia, depression, anxiety, Parkinson's disease, drug addiction, erectile dysfunction and urinary incontinence. Thus, there is a great interest in developing potent and selective 5-HT_2C receptor modulators.

Areas covered in this review: This review article highlights the research progress in 5-HT_2C receptor modulators published in the patent literature between January 2003 and June 2010, giving emphasis to the medicinal chemist's standpoint.

What the reader will gain: Readers will rapidly gain an overview of the various 5-HT_2C receptor modulators reported in the patent literature in the past 8 years. Furthermore, the readers will learn which structure type can interact with the 5-HT_2C receptor. In addition, the readers will be aware of the pharmaceutical companies that have been the main players in the field.

Take home message: There is substantial evidence supporting the concept that a selective 5-HT_2C receptor modulator should provide benefit in the treatment of a variety of CNS disorders. Although research efforts have identified several promising 5-HT_2C receptor modulators that display high functional selectivity, further clinical efficacy and safety data are needed to prove their actual clinical utility. Therefore, the query for selectively acting 5-HT_2C receptor modulators is still ongoing.     

Potential of transglutaminase 2 as a therapeutic target

Importance of the field: Increased expression and activity of transglutaminase 2 – a calcium-dependent enzyme which catalyzes protein cross-linking, polyamination or deamidation at selective glutamine residues – are involved in the etiopathogenesis of several pathological conditions, such as neurodegenerative disorders, autoimmune diseases and inflammatory diseases. Inhibition of enzyme activity has potential for therapeutic management of these diseases.

Areas covered in this review: The major results achieved in the last twelve years of research in the field of inhibition of tranglutaminase activity using cell cultures as well as in vivo models of high-social-impact or widespread diseases, such as CNS neurodegenerative disorders, celiac sprue, cancer and fibrotic diseases.

What the reader will gain: Beneficial effects of enzyme activity inhibition have been observed in neurodegeneration and fibrosis in vivo models by delivery of the competitive inhibitor cystamine and more recently designed inhibitors, such as thiomidaziolium or norleucine derivatives, which irreversibly bind the active site cysteine residue. Transglutaminase 2 targeting with specific antibodies has also been shown to be a promising tool for celiac disease treatment.

Take home message: New insights from transglutaminase inhibition studies dealing with side effects of in vivo administration of pan-transglutaminase inhibitors will help in design of novel therapeutic approaches to various diseases.     

Brain-derived neurotrophic factor as a driving force behind neuroplasticity in neuropathic and central sensitization pain: a new therapeutic target?

Introduction: Central sensitization is a form of maladaptive neuroplasticity underlying many chronic pain disorders, including neuropathic pain, fibromyalgia, whiplash, headache, chronic pelvic pain syndrome and some forms of osteoarthritis, low back pain, epicondylitis, shoulder pain and cancer pain. Brain-derived neurotrophic factor (BDNF) is a driving force behind neuroplasticity, and it is therefore crucial for neural maintenance and repair. However, BDNF also contributes to sensitization of pain pathways, making it an interesting novel therapeutic target.

Areas covered: An overview of BDNF’s sensitizing capacity at every level of the pain pathways is presented, including the peripheral nociceptors, dorsal root ganglia, spinal dorsal horn neurons, and brain descending inhibitory and facilitatory pathways. This is followed by the presentation of several potential therapeutic options, ranging from indirect influencing of BDNF levels (using exercise therapy, anti-inflammatory drugs, melatonin, repetitive transcranial magnetic stimulation) to more specific targeting of BDNF’s receptors and signaling pathways (blocking the proteinase-activated receptors 2–NK-κβ signaling pathway, administration of phencyclidine for antagonizing NMDA receptors, or blockade of the adenosine A2A receptor).

Expert opinion: This section focuses on combining pharmacotherapy with multimodal rehabilitation for balancing the deleterious and therapeutic effects of BNDF treatment in chronic pain patients, as well as accounting for the complex and biopsychosocial nature of chronic pain.     

Patent Update: Recent Advances in Antifungal Agents

Summary

Novelty: A novel series of tricyclicquinoxalinediones is claimed. These compounds are described as potent antagonists at strychnine-insensitive glycine modulatory sites of NMDA receptors. They may be useful in the treatment or prevention of a number of CNS disorders including neurodegenerative disorders, pain, depression and schizophrenia.

Biology: No biological data are provided, although the compounds are stated to have been evaluated for both [³H]-MK801 and [³H]-glycine binding.

Chemistry: One hundred and forty-four compounds are given as examples with full experimental and spectral details. No preferred compounds are described or named within the claims. One of the examples is 9-bromo-5-carboxy-6,7-dihydro-lH, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione.     

Emerging drugs for neuropathic pain

Introduction: Neuropathic pain is a costly and disabling condition, which affects up to 8% of the population. Available therapies often provide incomplete pain relief and treatment-related side effects are common. Preclinical neuropathic pain models have facilitated identification of several promising targets, which have progressed to human clinical phases of evaluation.

Areas covered: A systematic database search yielded 25 new molecular entities with specified pharmacological mechanisms that have reached Phase II or III clinical trials. These include calcium channel antagonists, vanilloid receptor antagonists, potassium channel agonists, NMDA antagonists, novel opioid receptor agonists, histamine H3 receptor antagonists, a novel sodium channel antagonist, serotonin modulators, a novel acetylcholine receptor agonist, α-2b adrenoreceptor agonist, cannabinoid CB2 receptor agonist, nitric oxide synthase inhibitor, orexin receptor antagonist, angiotensin II 2 antagonist, imidazoline I2 receptor agonist, apoptosis inhibitor and fatty acid amide hydrolase inhibitor.

Expert opinion: Although the diversity of pharmacological mechanisms of interest emphasise the complexity of neuropathic pain transmission, the considerable number of agents under development reflect a continued enthusiasm in drug development for neuropathic pain. Ongoing enhancements in methodology of both preclinical and clinical research and closer translation in both directions are expected to more efficiently identify new agents, which will improve the management of neuropathic pain.     

Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatric disorders

Introduction: Current drugs for the treatment of psychiatric or neurodegenerative disorders have limitations. Psychotherapeutic drugs such as typical and atypical antipsychotics, tricyclic antidepressants and selective monoamine reuptake inhibitors, aim to normalize the hyper- or hypo-neurotransmission of monoaminergic systems. Despite their contribution to the outcomes of psychiatric patients, these agents often exert severe side effects and require chronic treatments to promote amelioration of symptoms. Drugs available for the treatment of neurodegenerative disorders are severely limited.

Areas covered: Recent evidence that has shed light on sigma-1 receptor ligands, which may serve as a new class of antidepressants or neuroprotective agents. Sigma-1 receptors are novel ligand-operated molecular chaperones regulating signal transduction, ER stress, cellular redox, cellular survival and synaptogenesis. Selective sigma-1 receptor ligands exert rapid antidepressant-like, anxiolytic, antinociceptive and robust neuroprotective actions in preclinical studies. Recent studies that suggest that reactive oxygen species might play a role as signal integrators downstream of Sig-1Rs are also covered.

Expert opinion: The advances in sigma receptor research in the last decade have begun to elucidate the intracellular signal cascades upstream and downstream of sigma-1 receptors. The novel ligand-operated properties of the sigma-1 receptor chaperone may enable interventions by which stress-related cellular systems can be pharmacologically controlled.     

Targeting neuroinflammation for therapeutic intervention in neurodegenerative pathologies: a role for the peptide analogue of thymulin (PAT)

Introduction: Inflammation has a vital task in protecting the organism, but when deregulated, it can have serious pathological consequences. The central nervous system (CNS) is capable of mounting immune and inflammatory responses, albeit different from that observed in the periphery. Neuroinflammation, however, can be a major contributor to neurodegenerative diseases and constitute a major challenge for medicine and basic research.

Areas covered: Both innate and adaptive immune responses normally play an important role in homeostasis within the CNS. Microglia, astrocytes and neuronal cells express a wide array of toll-like receptors (TLR) that can be upregulated by infection, trauma, injuries and various exogenic or endogenic factors. Chronic hyper activation of brain immune cells can result in neurotoxic actions due to excessive production of several pro-inflammatory mediators. Several studies have recently described an important role for targeting receptors such as nicotinic receptors located on cells in the CNS or in other tissues for the control of inflammation.

Expert opinion: Thymulin and its synthetic peptide analogue (PAT) appear to exert potent anti-inflammatory effects at the level of peripheral tissues as well as at the level of the brain. This effect involves, at least partially, the activation of cholinergic mechanisms.