Innovative strategies in the diagnosis and treatment of tuberculosis: a patent review (2014–2017)

Introduction: Tuberculosis (TB) is a disease caused due to an infection of Mycobacterium tuberculosis (M TB) bacilli affecting millions of people worldwide. It is the ninth leading cause of death and ranks above the HIV/AIDS. The unique intracellular life cycle, more dangerous drug-resistant forms of bacilli, and insufficient investments in the TB research and development hindered the occurrence of optimum diagnostic, preventive, and treatment strategy against this disease.

Areas covered: The aim of this review is to provide an update and overview of the current trends in the diagnosis, prevention, and treatment of the disease. It summarizes a recent patent literature (2014–2017) available on the same.

Expert opinion: Some questions like ‘why most of these inventions do not reach up to the market for public use? Are these inventions being explored only to get a financial return to a particular industry or do they have any societal benefit?’ emphatically come to mind. Together with the efforts taken by various governmental and nongovernmental organizations, a public awareness about the recent advancements in the diagnosis and treatment of the disease is of the highest importance to make ‘the end of TB’ from the universe.     

2-Indolinone a versatile scaffold for treatment of cancer: a patent review (2008–2014)

Introduction: 2-Indolinone is a well-known aromatic heterocyclic organic compound. A lot of work has been done on this bicyclic structure by academic and company researchers to synthesize compounds directed to a plethora of molecular targets in order to discover new drug leads. This review presents up-to-date information in the field of cancer therapy research based on this small building block.

Areas covered: The present review gives an account of the recent patent literature (2008–2014) describing the discovery of 2-indolinone derivatives with selected therapeutic activities. In this period, a large amount of patents were published on this topic. We have limited the analysis to 37 patents on 2-indolinone derivatives having potential clinical application as chemotherapeutic agents. In this review, the therapeutic applications of 2-indolinone derivatives for the treatment of cancer reported in international patents have been discussed.

Expert opinion: 2-Indolinone is the scaffold of the compounds considered from a medicinal chemistry perspective. Many of them have been developed and marketed for therapeutic use. In cancer chemotherapy, progress has been made in designing selective 2-indolinone derivatives. Some of them show preclinical efficacy. However, 2-indolinone has not exhausted all of its potential in the development of new compounds for clinical applications and remains a great tool for future research.     

Synthetic drugs for the treatment of vitiligo: a patent review (2010–2015)

Introduction: Vitiligo is one of the most important acquired depigmentation disorders, with an average worldwide prevalence of 0.5–2.0%. The exact etiology of vitiligo is not fully understood, but the principle theories focus on the mechanism responsible for the destruction of melanocytes, which is proposed to be autoimmune, neurogenic, or self-destructive. There is no cure for vitiligo and the results of current treatments vary between individuals, being unsatisfactory in most cases. Despite being a cosmetic disease, the disorder can be psychologically devastating and stigmatizing.

Areas covered: In this review, the authors summarize new synthetic drugs for the treatment of vitiligo developed between 2010 and 2015, which include MC1 R agonists and peptides, as well as considering new approaches and strategies using existing drugs.

Expert opinion: In conclusion, we found significant advancement in this field of research, demonstrating the growing interest of academic and industrial groups in developing successful products for the treatment of vitiligo. New therapeutic options could contribute to improving the quality of life of patients and advance the search for a truly effective treatment of vitiligo.     

Chymase inhibitors for the treatment of cardiac diseases: a patent review (2010–2018)

ABSTRACT

Introduction: Chymase is primarily found in mast cells (MCs), fibroblasts, and vascular endothelial cells. MC chymase is released into the extracellular interstitium in response to inflammatory signals, tissue injury, and cellular stress. Among many functions, chymase is a major extravascular source for angiotensin II (Ang II) generation. Several recent pre-clinical and a few clinical studies point to the relatively unrecognized fact that chymase inhibition may have significant therapeutic advantages over other treatments in halting progression of cardiac and vascular disease.

Area covered: The present review covers patent literature on chymase inhibitors for the treatment of cardiac diseases registered between 2010 and 2018.

Expert opinion: Increase in cardiac MC number in various cardiac diseases has been found in pathological tissues of human and experimental animals. Meta-analysis data from large clinical trials employing angiotensin-converting enzyme (ACE) inhibitors show a relatively small risk reduction of clinical cardiovascular endpoints. The disconnect between the expected benefit associated with Ang II blockade of synthesis or activity underscores a greater participation of chymase compared to ACE in forming Ang II in humans. Emerging literature and a reconsideration of previous studies provide lucid arguments to reconsider chymase as a primary Ang II forming enzyme in human heart and vasculature.     

Telomerase inhibitors: a patent review (2010–2015)

Introduction: Telomerase is a ribonucleoprotein that catalyses the addition of telomeric repeat sequences (having the sequence 5′-TTAGGG-3′ in humans) to the ends of chromosomes. Telomerase activity is detected in most types of human tumours, but it is almost undetectable in normal somatic cells. Therefore, telomerase is a promising therapeutic target. To date, the known inhibitors of telomerase include nucleoside analogues, oligonucleotides and G-quadruplex stabilizers. This review highlights recent advances in our understanding of telomerase inhibitors, the relationships between telomerase inhibitors, cancer, and fields such as inflammation.

Areas covered: This review summarizes new patents published on telomerase inhibitors from 2010 to 2015.

Expert opinion: The review provides a brief account of the background, development, and on-going issues involving telomerase inhibitors. In particular, this review emphasizes imetelstat (GRN163L) and some typical G-quadruplex stabilizers that participate in telomerase inhibition. Overall, the research scope of antineoplastic is becoming broader and telomerase inhibitors have been shown to be a promising therapeutic target. Therefore, novel antineoplastic agents with greater activity and higher specificity must be developed.     

Therapeutic potential of oxazole scaffold: a patent review (2006–2017)

ABSTRACT

Introduction: Oxazoles are oxygen and nitrogen containing five membered heterocyclic ring systems that are present in various anticancer, antimicrobial, antihyperglycemic, anti-inflammatory agents etc. of natural origin. These pharmacologically active oxazole derivatives have attracted numerous researchers to explore this scaffold for the design and development of newer potential therapeutic agents. A large number of synthetic oxazole containing molecules have been reported over the period that exhibited wide spectrum of pharmacological profiles. Some of them have shown promising therapeutic potential and have qualified for both preclinical and clinical evaluations.

Areas covered: In this review, the patents (published during 2006–2017) focusing on the biological potential of oxazoles have been covered. Therapeutic applications and various techniques/assays employed for the in vitro/in vivo evaluation of patented derivatives have been discussed majorly.

Expert opinion: Chemically oxazole offers three positions for substitution. These substituted oxazole derivatives of natural as well as synthetic origin have numerous pharmacological applications including anticancer, anti-Alzheimer’s, anti-hyperglycemic, anti-inflammatory, antibacterial etc. Their pharmacological actions are mainly mediated through enzyme/receptor involved in the particular disease. The flexible nature of this ligand for various molecular level targets (enzyme/receptor) make this heterocylce an attractive scaffold for development of effective and clinically relevant oxazole containing therapeutic agents.     

Small molecules and antibodies for the treatment of psoriasis: a patent review (2010–2015)

Introduction: Psoriasis is a chronic condition whose therapeutic armamentarium is increasingly being discussed, particularly when compared to past decades. The use of biologic agents has profoundly changed the history of this disease, as well as the management of psoriatic patients. Due to the enormous interest in psoriasis, as demonstrated within the scientific community and pharmaceuticals, new therapeutic targets have been identified and novel patented therapeutics are being tested.

Areas covered: This review sought to give an overview of small molecules and antibodies patented in the last five years for the treatment of psoriasis. Therapeutic agents either in the early or advanced phase of development have been described, primarily based on a systematic search using the PubMed Medline database.

Expert opinion: Though the recent introduction of new antipsoriatic agents has facilitated the management of long-term psoriasis, there is still a strong desire for alternative therapeutic options. Indeed, there remain unmet needs regarding safety and efficacy of psoriasis treatment that should be addressed. In this context, recently patented drugs may prove valid, interesting, and promising within the therapeutic paradigm.     

Progress in acetylcholinesterase reactivators and in the treatment of organophosphorus intoxication: a patent review (2006–2016)

Introduction: organophosphorus compounds act as irreversible inhibitors of the vital enzyme acetylcholinesterase (AChE). this leads in the accumulation of acetylcholine (ACh) leading to cholinergic crisis and death. The main therapeutic approach is based on immediate administration of an ache reactivator as an antidote enabling recovery of the ache function.

Areas covered: This review covers the development of AChE reactivators in order to introduce a new efficient drug that will overcome significant failures of common antidotes. Further options together with methods of detection are also discussed in order to assure a complete insight into the treatment of intoxication.

Expert opinion: Since organophosphates belong to the most toxic chemical warfare agents, efficient antidotes are a matter of importance. The solution of how to limit the basic drawbacks of clinically used reactivators remained a spotlight for many researches worldwide. Recent strategies of the treatment of OP exposure bring us new possibilities which may overcome classic antidotes. The importance of detection of OP also has to be taken into consideration. Especially, with the fast spreading toxic effect when death can occur within minutes.     

Inhibitors of cathepsin K: a patent review (2004 – 2010)

Introduction: Cathepsin K is a lysosomal cysteine protease involved in osteoclast-mediated bone resorption. Inhibition of cathepsin K represents a potentially attractive therapeutic approach for treating diseases characterized by excessive bone resorption, such as osteoporosis.

Areas covered: The present review provides an overview of low molecular weight cathepsin K inhibitors published in the patent literature from July 2004 to 2010. Different chemotypes are surveyed and listed according to electrophilic warhead type. Relevant information from original research articles in peer-reviewed journals and clinical investigations is also described.

Expert opinion: Between 2004 and 2010, more than 50 patent applications have appeared, underlining the continued interest in small molecule cathepsin K inhibition for therapeutic intervention. Most compounds claimed are peptide-derived inhibitors displaying a reversible binding nitrile or ketone warhead. The success of these compounds in the clinic will be determined by the selectivity that can be achieved against other off-target cathepsin. In this respect, eliminating lysosomotropic characteristics may prove to be crucial in the design of selective cathepsin K inhibitors. During the review period, ONO-5334 and odanacatib have progressed to Phase II and Phase III clinical trials, respectively. The results of these studies are eagerly awaited and may determine the future of these agents as disease-modifying therapeutics.     

The use of terpenes and derivatives as a new perspective for cardiovascular disease treatment: a patent review (2008–2018)

Introduction: Terpenes are a class of secondary metabolites that can be found in a variety of animal and plants species. They are considered the most structurally diversified and abundant of all natural compounds. Several studies have shown the application of terpenes, such as carvacrol, linalool, and limonene in many pharmaceutical and medicinal fields, including cardiovascular disorders, the leading cause of death worldwide. Areas covered: In this review, the authors outlined patents from the last 10 years relating to the therapeutic application of terpenes for the treatment and/or prevention of cardiovascular diseases found in different databases, emphasizing the possibility of these compounds becoming new drugs that may help to decrease the burden of these disorders. Expert opinion: There has been a growing awareness over recent years of the therapeutic use of terpenes and their derivatives as new pharmaceutical products. Patents involving the use of terpenes have been especially important in the technological development of new strategies for the treatment of cardiovascular diseases by bringing new scientific knowledge into the pharmaceutical industry. Therefore, the development of biotechnologies using natural products should be encouraged in order to increase the variety of drugs available for the treatment of cardiovascular diseases.     

A patent review of butyrylcholinesterase inhibitors and reactivators 2010–2017

Introduction: Butyrylcholinesterase (BuChE) has obtained a renewed interest as therapeutic target in Alzheimer’s disease (AD), when changes in BuChE activity and expression along disease progression were highlighted as well as correlation between BuChE levels and cognitive function.

Areas covered: During the last eight years, fourteen patents on BuChE inhibitors (BuChEI) have been submitted. Only three of them relate to BuChE selective inhibitors, while four of them focus on multitarget inhibitors which address different key pathological factors other than BuChE. Two patents report on non-selective acetylcholinesterase (AChE)/BuChE inhibitors, while four patents deal with natural compounds and their derivatives. One patent relates to antitoxic agents to treat exposure to ChEI pesticides and nerve agents.

Expert opinion: Increasing evidence supports BuChE as a more beneficial target in moderate-to-severe forms of AD in comparison to the well-known AChE. However, hitting a single pathological target is likely not sufficient to halt the disease progression. Therefore, patented BuChE inhibitors with a multifunctional profile may open new therapeutic avenues, since the additional activities could reinforce the therapeutic effects. Unfortunately, in vivo studies are limited and key parameters, such as ADMET data, are missing. This lack of information makes difficult to forecast the development of patented BuChEIs into effective drug candidates.     

Norcantharidin analogues: a patent review (2006 – 2010)

Introduction: Norcantharidin (7-oxabicyclo [2.2.1] heptane-2,3-dicarboxylic anhydride) is the demethylated form of cantharidin. Norcantharidin not only has strong anticancer activity, but also eliminates most side-effects in the urinary system, does not cause myelosuppression and increases the number of white blood cells. With structural modification, norcantharidin analogues show potential anticancer activities.

Areas covered: A comprehensive patent review of norcantharidin analogues from 2006 to 2010 is presented. Protein phosphatase 1, 2A, 2B and 5 inhibitors are described. The review summarizes the new compounds and lays the foundation for seeking more effective anticancer compounds.

Expert opinion: Although norcantharidin has improved activity and toxicity, the effects routinely do not satisfy the current clinical need. Exploring better analogues is vital for changing the current situation, but norcantharidin is a good lead compound.     

Acridine derivatives: a patent review (2009 – 2010)

Introduction: Acridines are highly important heterocyclic compounds with immense biological significance as they act as the central core of antitumor, anti-protozoan, antiviral and multi-drug resistance modulating agents. The tricyclic aromatic structure of acridine is primarily responsible for its intercalation with DNA by controlling its biological profile and the substitution pattern of the molecule, which leads to several other applications.

Areas covered: In this review, acridine-based functional molecules and patents of acridine derivatives filed from 2009 to 2010 are discussed. The latest information about the medical importance of new acridine-based molecules is also discussed (e.g., materials with sensing and electrical/thermal properties).

Expert opinion: The tricyclic aromatic heterocyclic structure of acridine has a lot of potential for biological and material utilization. The versatility of fluorescent acridines could be further enhanced by introducing amino-acid chains or other polar substituents on the central moiety, which due to increased water solubility could increase their effectiveness under physiological conditions.     

Antifolate agents: a patent review (2006 – 2010)

Introduction: For > 50 years, drugs targeting the folate pathway have significantly impacted disease treatment as anticancer, antimicrobial and immunomodulatory agents. The discovery of novel antifolate agents with improved properties and superior activities remains an attractive strategy, both in academia and the pharmaceutical industry.

Areas covered: This review surveys the patent literature from 2006 to 2010 for small molecule inhibitors of enzymatic targets in the folate biosynthetic pathway.

Expert opinion: The pursuit of antifolates as anticancer and antimicrobial agents continues to be an active area of research. New patent disclosures reveal novel antifolate scaffolds, antifolates with improved drug-like properties and new strategies to effectively target cancer cells. The continued use of high resolution structural information has guided the discovery of several compounds. Owing to the need for high levels of potency and selectivity, especially in targeting pathogenic species, the use of high resolution crystal structures remains an important tool to guide the design of novel antifolates. Interestingly, the patents disclosing novel compounds were ones where X-ray crystallography was an integral component of the design process. Finally, a variety of new structures have been reported that may play an important role in the future development of therapeutic antifolates.     

Antifolate agents: a patent review (2010 – 2013)

Introduction: The folate biosynthetic pathway, responsible for the de novo synthesis of thymidine and other key cellular components, is essential in all life forms and is especially critical in rapidly proliferating cells. As such, druggable targets along this pathway offer opportunities to impact many disease states such as cancer, infectious disease and autoimmune disease. In this article, recent progress on the development of antifolate compounds is reviewed.

Areas covered: The evaluation of the patent literature during the period 2010 – 2013 focused on any compounds inhibiting recognized targets on the folate biosynthetic pathway.

Expert opinion: The folate pathway constitutes a well-validated and well-characterized set of targets; this pathway continues to elicit considerable enthusiasm for new drug discovery from both academic and industrial pharmaceutical research groups. Within the pathway, the enzymes dihydrofolate reductase and thymidylate synthase persist as the most attractive targets for new drug discovery for the treatment of cancer and infectious disease. Importantly, new potential targets for antifolates such as those on the purine biosynthetic pathway have been recently explored. The use of structure-based drug design is a major aspect in modern approaches to these drug targets.     

Dendrimer and cancer: a patent review (2006 – present)

Introduction: Dendrimers were widely used in cancer diagnosis and therapy during the past decade. The surface functionalities allow bioactive molecules such as imaging probes, therapeutic compounds, targeting ligands to be present on dendrimer surface in a multivalent fashion. In addition, the interior pockets as well as the charged surface of dendrimer can be encapsulated/bound with anti-cancer drugs or therapeutic DNAs/siRNAs.

Areas covered: The combination of dendrimer chemistry and new cancer therapy techniques such as radiotherapy, photodynamic therapy, neuron capture therapy, and photothermal therapy provides promising strategies in future cancer therapy. Here, we focused on recent advances on this topic in the patents (2006 – present) and discussed the advantages of dendrimer technology in these inventions.

Expert opinion: The challenges and perspectives of dendrimer-based theranostics for cancer diagnosis and therapy are discussed. Future efforts in this area should be focused on designing materials to solve problems such as cancer metastasis, multidrug resistance (MDR) in cancer cells, and early-stage cancer diagnosis.     

Kinesin spindle protein inhibitors in cancer: a patent review (2008 – present)

Introduction: Inhibition of kinesin spindle protein (KSP) has emerged as a novel and validated therapeutic strategy against cancers. A lot of new KSP inhibitors have been identified in recent years and some of them have entered clinical trials. This may provide more selections in future cancer therapy.

Areas covered: In the present review, the authors will describe the most recent classes of KSP inhibitors by reviewing about 96 literatures in which 24 patent applications were included from 2008 to now.

Expert opinion: Many new KSP inhibitors have been discovered that act either by binding in an allosteric site of KSP or by ATP competitive inhibition. There are several ATP non-competitive KSP inhibitors entering clinical investigation. Although they were both well tolerated and showed acceptable pharmacokinetic profiles, limited clinical response was always the problem. Mutation of the binding pocket was also a hindrance in the development of these allosteric inhibitors. The appearance of ATP competitive KSP inhibitors was considered to be able to overcome mutation-mediated resistance to the allosteric inhibitors, which could be a new approach for the development of novel KSP inhibitors.     

A patent review of RAF kinase inhibitors (2010–2018)

ABSTRACT

Introduction: RAF kinase inhibitors block and regulate RAS/RAF/MEK/ERK signaling, which is a key to tumor treatment. At present, although RAF kinase inhibitors have good efficacy, there are few such drugs with low toxicity, and thus, it is urgent to find novel RAF kinase inhibitors associated with higher activity and fewer adverse reactions. This review highlights the anti-tumor effects of several published RAF kinase inhibitors and might be helpful in providing new ideas for the development of novel drug candidates in the future.

Areas covered: This article covers the pertinent literature published on RAF kinase inhibitors from 2010 to 2018, as well as the potential use of these compounds as therapeutics for cancer.

Expert opinion: To date, many RAF kinase inhibitors with different structures have been studied, many of which have prominent inhibitory activities toward RAF kinase. Further, the specificity of these drugs offers hope for the targeted therapy of tumors. Although RAF kinase inhibition has achieved promising results for the treatment of many cancers, overcoming limitations associated with drug resistance and safety comprises a new direction for the optimization and improvement of RAF kinase inhibitors.