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.     

Meisoindigo,but not its core chemical structure indirubin,inhibits zebrafish interstitial leukocyte chemotactic migration

Context: Inflammatory disease is a big threat to human health. Leukocyte chemotactic migration is required for efficient inflammatory response. Inhibition of leukocyte chemotactic migration to the inflammatory site has been shown to provide therapeutic targets for treating inflammatory diseases.

Objective: Our study was designed to discover effective and safe compounds that can inhibit leukocyte chemotactic migration, thus providing possible novel therapeutic strategy for treating inflammatory diseases.

Materials and methods: In this study, we used transgenic zebrafish model (Tg:zlyz-EGFP line) to visualize the process of leukocyte chemotactic migration. Then, we used this model to screen the hit compound and evaluate its biological activity on leukocyte chemotactic migration. Furthermore, western blot analysis was performed to evaluate the effect of the hit compound on the AKT or ERK-mediated pathway, which plays an important role in leukocyte chemotactic migration.

Results: In this study, using zebrafish-based chemical screening, we identified that the hit compound meisoindigo (25?μM, 50?μM, 75?μM) can significantly inhibit zebrafish leukocyte chemotactic migration in a dose-dependent manner (p?=?0.01, p?=?0.0006, p?p?=?0.43). Furthermore, our results unexpectedly showed that indirubin, the core structure of meisoindigo, had no significant effect on zebrafish leukocyte chemotactic migration (p?=?0.6001). Additionally, our results revealed that meisoindigo exerts no effect on the Akt or Erk-mediated signalling pathway.

Discussion and conclusion: Our results suggest that meisoindigo, but not indirubin, is effective for inhibiting leukocyte chemotactic migration, thus providing a potential therapeutic agent for treating inflammatory diseases.     

Filled carbon nanotubes in biomedical imaging and drug delivery

Introduction: Carbon nanotubes have been advocated as promising candidates in the biomedical field in the areas of diagnosis and therapy. In terms of drug delivery, the use of carbon nanotubes can overcome some limitations of ‘free’ drugs by improving the formulation of poorly water-soluble drugs, allowing targeted delivery and even enabling the co-delivery of two or more drugs for combination therapy. Two different approaches are currently being explored for the delivery of diagnostic and therapeutic agents by carbon nanotubes, namely attachment of the payload to the external sidewalls or encapsulation into the inner cavities. Although less explored, the latter confers additional stability to the chosen diagnostic or therapeutic agents, and leaves the backbone structure of the nanotubes available for its functionalization with dispersing and targeting moieties. Several drug delivery systems and diagnostic agents have been developed in the last years employing the inner tubular cavities of carbon nanotubes.

Areas covered: The research discussed in this review focuses on the use of carbon nanotubes that contain in their interior drug molecules and diagnosis-related compounds. The approaches employed for the development of such nanoscale vehicles along with targeting and releasing strategies are discussed.

Expert opinion: The encapsulation of both biomedical contrast agents and drugs inside carbon nanotubes is further expanding the possibilities to allow an early diagnosis and treatment of diseases.     

Emerging drugs for the treatment of bone metastasis

Introduction: Bone metastases are virtually incurable resulting in significant disease morbidity, reduced quality of life and mortality. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Increased understanding of the pathogenesis of bone disease has led to the discovery and clinical utility of bone-targeted agents other than bisphosphonates and denosumab, currently, the standard of care in this setting.

Areas covered: In this review, we present the recent advances in molecular targeted therapies focusing on therapies that inhibit bone resorption and/or stimulate bone formation and novel anti-tumoral agents that exerts significant effects on skeletal metastases, nowadays available in clinical practice or in phase of development.

Expert opinion: New emergent bone target therapies radium-223, mTOR inhibitors, anti-androgens have demonstrated the ability to increase overall survival in bone metastatic patients, other compounds, such as ET-1 and SRC inhibitors, up to now failed to clearly confirm in clinical trials their promising preclinical data.     

5-Lipoxygenase inhibitors: a review of recent developments and patents

Importance to the field: Leukotrienes (LTs) are pivotal lipid mediators of inflammation and allergy and results from recent studies also suggest roles of LTs in cardiovascular diseases, cancer and osteoporosis. 5-Lipoxygenase (5-LO) catalyzes the first step in the biosynthesis of LTs from arachidonic acid, and based on the multiple potent pathophysiological actions of LTs, the pharmacological intervention with 5-LO is a challenge in the development of therapeutics.

Areas covered in this review: We first summarize the biochemical regulation of 5-LO and the general pharmacological concepts in 5-LO inhibition by currently available compounds, and subsequently we report recent developments deduced from recent scientific publications and patents.

What the reader will gain: A comprehensive overview about the different molecular pharmacological strategies to inhibit 5-LO and the most successful previous 5-LO inhibitors. The review also gives insights into novel concepts, for example, dual prostaglandin/LT synthesis inhibition and reveals novel compounds patented or developed within the past 5 years.

Take home message: Despite the increasing therapeutic indications of anti-LT therapy, the progress in the development of novel 5-LO inhibitors is moderate. However, novel molecular concepts in the intervention with LT biosynthesis seem promising.     

QSAR studies in the discovery of novel type-II diabetic therapies

Introduction: Type-II diabetes mellitus (T2DM) is a complex chronic disease that represents a major therapeutic challenge. Despite extensive efforts in T2DM drug development, therapies remain unsatisfactory. Currently, there are many novel and important antidiabetic drug targets under investigation by many research groups worldwide. One of the main challenges to develop effective orally active hypoglycemic agents is off-target effects. Computational tools have impacted drug discovery at many levels. One of the earliest methods is quantitative structure–activity relationship (QSAR) studies. QSAR strategies help medicinal chemists understand the relationship between hypoglycemic activity and molecular properties. Hence, QSAR may hold promise in guiding the synthesis of specifically designed novel ligands that demonstrate high potency and target selectivity.

Areas covered: This review aims to provide an overview of the QSAR strategies used to model antidiabetic agents. In particular, this review focuses on drug targets that raised recent scientific interest and/or led to successful antidiabetic agents in the market. Special emphasis has been made on studies that led to the identification of novel antidiabetic scaffolds.

Expert opinion: Computer-aided molecular design and discovery techniques like QSAR have a great potential in designing leads against complex diseases such as T2DM. Combined with other in silico techniques, QSAR can provide more useful and rational insights to facilitate the discovery of novel compounds. However, since T2DM is a complex disease that includes several faulty biological targets, multi-target QSAR studies are recommended in the future to achieve efficient antidiabetic therapies.     

Current options for drug delivery to the spinal cord

Introduction: Spinal cord disorders (SCDs) are among the most devastating neurological diseases, due to their acute and long-term health consequences, the reduced quality of life and the high economic impact on society. Here, drug administration is severely limited by the blood–spinal cord barrier (BSCB) that impedes to reach the cord from the bloodstream. So, developing a suitable delivery route is mandatory to increase medical chances.

Areas covered: This review provides an overview of drug delivery systems used to overcome the inaccessibility of the cord. On one side, intrathecal administration, either with catheters or with biomaterials, represents the main route to administer drugs to the spinal cord; on the other side, more recent strategies involve chemical or electromagnetic disruption of the barrier and synthesis of novel functionalized compounds as nanoparticles and liposomes able to cross BSCB.

Expert opinion: Both the multifactorial pathological progression and the restricted access of therapeutic drugs to the spine are probably the main reasons behind the absence of efficient therapeutic approaches for SCDs. Hence, very recent highlights suggest the use of original strategies to overcome the BSCB, and new multidrug delivery systems capable of local controlled release of therapeutic agents have been developed. These issues can be addressed by using nanoparticles technology and smart hydrogel drug delivery systems, providing an increased therapeutic compound delivery in the spinal cord environment and multiple administrations able to synergize treatment efficacy.     

New and developing therapies for AL amyloidosis

Introduction: Systemic light-chain (AL) amyloidosis is an infiltrative disorder associated with an underlying plasma cells dyscrasia, in which monoclonal immunoglobulin light chains accumulate in an abnormal misfolded form as amyloid fibrils in the extracellular space. Symptoms and prognosis are governed by which organs are affected, and cardiac involvement is the major determinant of survival. Diagnosis requires demonstration of amyloid deposition and confirmation of the fibril protein type.

Areas covered: This review will focus on the available treatments for systemic AL amyloidosis and on new drug targets and therapeutic approaches.

Expert opinion: At present, the choice of upfront treatment lies between autologous stem cell transplantation (ASCT) and combination chemotherapy. Chemotherapy agents include dexamethasone, melphalan, cyclophosphamide, thalidomide, bortezomib, lenalidomide, bendamustine in various combinations. Few randomized controlled trials have been performed in AL amyloidosis and treatment has been substantially influenced by clinical practice in myeloma. It has become clear that the best prospects of survival and preservation or improvement in amyloid related organ function require as near complete suppression as possible of the underlying hematological disorder. Future directions include therapies designed to target amyloid deposits directly, in particular anti-amyloid antibodies which are now well advanced in development and are showing great potential.     

Latent cytokines for targeted therapy of inflammatory disorders

Introduction: The use of cytokines as therapeutic agents is important, given their potent biological effects. However, this very potency, coupled with the pleiotropic nature and short half-life of these molecules, has limited their therapeutic use. Strategies to increase the half-life and to decrease toxicity are necessary to allow effective treatment with these molecules.

Areas covered: A number of strategies are used to overcome the natural limitations of cytokines, including PEGylation, encapsulation in liposomes, fusion to targeting peptides or antibodies and latent cytokines. Latent cytokines are engineered using the latency-associated peptide of transforming growth factor-β to produce therapeutic cytokines/peptides that are released only at the site of disease by cleavage with disease-induced matrix metalloproteinases. The principles underlying the latent cytokine technology are described and are compared to other methods of cytokine delivery. The potential of this technology for developing novel therapeutic strategies for the treatment of diseases with an inflammatory-mediated component is discussed.

Expert opinion: Methods of therapeutic cytokine delivery are addressed. The latent cytokine technology holds significant advantages over other methods of drug delivery by providing simultaneously increased half-life and localised drug delivery without systemic effects. Cytokines that failed clinical trials should be reassessed using this delivery system.     

Novel ferrocenyl-containing N-acetyl-2-pyrazolines inhibit in vitro angiogenesis and human lung cancer growth by interfering with F-actin stress fiber polimeryzation

Abstract

Cancer is a significant worldwide health problem generally because of lack of widespread and comprehensive early detection methods. Lung cancer is the leading cause of cancer deaths in men worldwide and the second leading cause of cancer deaths in women. To date, the available treatment regimens are not successful. For this reason, new targets for prevention and new agents for therapy need to be identified. The biological activities of some synthesized ferrocene-containing N-acetylated-2-pyrazoline compounds were studied for this article. Their cytotoxicity (by methyl thiazol tetrazolium assay), as well as apoptotic (by 4′6-diamidino-phenylindole and F-actin staining), antitumoral (colony-forming ability assay) and antiangiogenic activities (by tube formation), were evaluated for the first time on a human non-small-cell lung cancer (A549) cell line and a human umbilicial vein endothelial cell line. All compounds were cytotoxic, antitumoral and apoptotic against tumor cells in a dose-dependent manner. Compounds 2 and 3, which were noncytotoxic, could inhibit capillary vessel formation. Especially, N-acetyl-5-ferrocenyl-3-(2-thienyl)-2-pyrazoline (2) may be used in the development of therapeutic agents for angiogenic diseases and cancer.     

Coumarin derivatives: an updated patent review (2012 – 2014)

Introduction: Coumarins belong to the benzopyrones family. They are naturally plant-derived and synthetically taken polyphenolic substances, presenting a wide variety of biological activities and behaviours, supporting their use as therapeutic agents for multiple diseases. Their structural characteristics correlated to physicochemical properties seem to define the extent of the biological activity.

Areas covered: Recent patent publications (2012 – 2014), describing coumarins and their derivatives are analyzed. Synthesis, hybridization techniques and biological evaluation in vitro/in vivo, for example, antimitotic, antiviral, anticancer, cytotoxic, anti-acne and antioxidant coumarin macromolecule polymer agents are included. Furthermore, a wide range of pharmaceutical applications and pharmaceutical compositions are also summarized.

Expert opinion: Several natural and synthetic coumarins, hybrids and derivatives appear to have promising anticancer-antitumor activities. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action is well defined can serve as lead compounds for the design of new more potent molecules.     

Diuretics in clinical practice. Part I: mechanisms of action,pharmacological effects and clinical indications of diuretic compounds

Importance of the field: Diuretics are among the most important drugs of our therapeutic armamentarium and have been broadly used for >?50 years, providing important help towards the treatment of several diseases. Although all diuretics act primarily by impairing sodium reabsorption in the renal tubules, they differ in their mechanism and site of action and, therefore, in their specific pharmacological properties and clinical indications. Loop diuretics are mainly used for oedematous disorders (i.e., cardiac failure, nephrotic syndrome) and for blood pressure and volume control in renal disease; thiazides and related agents are among the most prescribed drugs for hypertension treatment; aldosterone-blockers are traditionally used for primary or secondary aldosteronism; and other diuretic classes have more specific indications.

Areas covered in this review: This article discusses the mechanisms of action, pharmacological effects and clinical indications of the various diuretic classes used in everyday clinical practice, with emphasis on recent knowledge suggesting beneficial effects of certain diuretics on clinical conditions distinct from the traditional indications of these drugs (i.e., heart protection for aldosterone blockers).

What the reader will gain: Reader will gain insights into the effective use of diuretic agents for various medical conditions, representing their established or emerging therapeutic indications.

Take home message: Knowledge of the pharmacologic properties and mechanisms of action of diuretic agents is a prerequisite for the successful choice and effective clinical use of these compounds.     

Thyromimetics: a review of recent reports and patents (2004 – 2009)

Importance of the field: Thyroid hormones are produced by the thyroid gland and peripheral tissues, and control metabolic rate, including oxygen consumption, lipid metabolism and the cardiovascular system, mainly through binding to and activating thyroid hormone receptors (TRs). Abnormal elevation or lowering of circulating thyroid hormone induces various physiological disorders. As candidates for the treatment of such diseases, various thyromimetics, such as subtype- or tissue-selective TR agonists and antagonists, have been developed.

Areas covered in this review: This review focuses on recent reports and patents covering thyromimetics, especially those published in the last 6 years.

What the reader will gain: In this review, we classify thyromimetics based on structure. The structures of most thyromimetic compounds are based on those of endogenous thyroid hormones, which consist of a biaryl ether skeleton substituted with iodine, α-alanine moiety and hydroxyl group at two benzene rings. Many thyromimetics have been developed by replacement of the polar group, changing the bridging oxygen, or introduction of heterocycles. This review provides an overview of the structure–activity relationship.

Take home message: Some thyromimetics are subtype- or tissue-selective TR agonists and antagonists, and such compounds have the potential to become novel therapeutic agents, especially in the field of metabolic diseases.     

Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism

The formation of well-ordered fibrillar protein deposits is common to a large group of amyloid-associated disorders. This group consists of several major human diseases such as Alzheimer's disease, Parkinson's disease, prion diseases, and type II diabetes. Currently, there is no approved therapeutic agent directed towards the formation of fibrillar assemblies, which have been recently shown to have a key role in the cytotoxic nature of amyloidogenic proteins. One important approach in the development of therapeutic agents is the use of small molecules that specifically and efficiently inhibit the aggregation process. Several small polyphenol molecules have been demonstrated to remarkably inhibit the formation of fibrillar assemblies in vitro and their associated cytotoxicity. Yet, the inhibition mechanism was mostly attributed to the antioxidative properties of these polyphenol compounds. Based on several observations demonstrating that polyphenols are capable of inhibiting amyloid fibril formation in vitro, regardless of oxidative conditions, and in view of their structural similarities we suggest an additional mechanism of action. This mechanism is assuming structural constraints and specific aromatic interactions, which direct polyphenol inhibitors to the amyloidogenic core. This proposed mechanism is highly relevant for future de novo inhibitors' design as therapeutic agents for the treatment of amyloid-associated diseases.     

Tumor vasculature as target for therapeutic intervention

Importance of the field: Solid tumors rely on efficient oxygen and nutrients transport for their growth, development and survival. Many tumors can stimulate new blood vessel formation. Because this angiogenic vasculature is aberrant from normal host vasculature, several strategies have been explored that specifically target tumor blood vessels.

Areas covered in this review: Over the past decade, many molecules that act on tumor vasculature have been identified. They can be divided into three groups based on their mechanism of action: i) antiangiogenic molecules cause tumor growth arrest; ii) vasoactive agents induce hyperabnormalization of the tumor vasculature, improving conventional drug accumulation in the tumor; iii) vascular disrupting agents that cause blood vessel congestion, resulting in massive secondary tumor cell necrosis. Many investigational drugs from these classes are currently being evaluated to assess their role in tumor therapy.

What the reader will gain: The underlying principle of each of the strategies is discussed, and the (pre)clinical results of the investigational drugs in this class are highlighted.

Take home message: To fully exploit the therapeutic potential of these drugs, it appears necessary to combine them with conventional anticancer agents, improve their selectivity for tumor vasculature, and develop biomarkers that predict the tumor sensitivity for these vascular strategies.     

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.