Cyclodextrins improving the physicochemical and pharmacological properties of antidepressant drugs: a patent review

Introduction: Depression is a serious mood disorder and is one of the most common mental illnesses. Despite the availability of several classes of antidepressants, a substantial percentage of patients are unresponsive to these drugs, which have a slow onset of action in addition to producing undesirable side effects. Some scientific evidence suggests that cyclodextrins (CDs) can improve the physicochemical and pharmacological profile of antidepressant drugs (ADDs). The purpose of this paper is to disclose current data technology prospects involving antidepressant drugs and cyclodextrins.

Areas covered: We conducted a patent review to evaluate the antidepressive activity of the compounds complexed in CDs, and we analyzed whether these complexes improved their physicochemical properties and pharmacological action. The present review used 8 specialized patent databases for patent research, using the term ‘cyclodextrin’ combined with ‘antidepressive agents’ and its related terms. We found 608 patents. In the end, considering the inclusion criteria, 27 patents reporting the benefits of complexation of ADDs with CDs were included.

Expert opinion: The use of CDs can be considered an important tool for the optimization of physicochemical and pharmacological properties of ADDs, such as stability, solubility and bioavailability.     

A patent review of the therapeutic potential of isoflavones (2012-2016)

Introduction: Isoflavones are well-studied natural products isolated from natural sources with interesting chemodiversity and possess a wide variety of biological effects. Moreover, chemical modifications based on the isoflavone scaffold, has generated synthetic chemodiversity to enhance the bioactivities of isoflavones.

Areas covered: The current review summarizes the discovery of new chemotherapeutic agents possessing the isoflavone skeleton. This review incorporates patents filed between 2012 and 2016 mostly related to anticancer, antidiabetic, antimicrobial, anti-HIV, anti-gastric ulcer, anti-gastritis, antiparasitic and some other biological effects demonstrated by isoflavone analogs.

Expert opinion: The number of interesting patents published during the five year period (2012–2016) on the therapeutic potential of isoflavones indicated the importance of this molecule. Natural isoflavones possess potent anticancer, anti-HIV and antidiabetic activities and chemical analogs of natural isoflavones increase the abovementioned biological effects. Additionally isoflavones have only been tested for a limited number of biological activities and thus future research should focus on additional biological activities viz., anti-inflammatory, antimalarial, and anti-leishmanial effects. However, the absence of SAR studies and in vivo data restricted the rational design of more potent isoflavone analogs and we believe that in order to get lead compounds, there needs to be a greater focus on SAR and in vivo studies.     

A patent review of two fruitful decades (1997-2016) of Isocoumarin research

Introduction: Isocoumarins comprise a six-membered oxygen heterocycle (α-pyranone) along with one aromatic ring and are known to possess interesting biological properties. During the last two decade (1997–2016), isocoumarin chemistry has attracted attention due to its biological and pharmaceutical effects viz., anticancer, anti-diabetic, antibacterial, antimalarial, and fungicidal effects.

Areas covered: This review covers the patents on the therapeutic activities of natural and synthetic isocoumarins over the last two decades (1997–2016). Moreover a number of international patents related to natural and synthetic isocoumarins along with their biological effects will be presented and discussed. Although a large number of patents have been published during the period of the review, the aim of this review is to focus on those important patents specifically related to microbial diseases, cancer, malaria, and diabetes.

Expert opinion: Isocoumarin and its synthetic analogs display a wide range of important pharmaceutical properties. Furthermore, isocoumarins have the potential to conjugate with other anticancer drugs which will synergistically increase the delivery and thus anticancer effects. Moreover, in order to get lead compounds, scientists should focus on the synthesis of halo and functionalized heterocyclic ring containing derivatives of isocoumarins as more potent drugs.     

Novel benzopyran derivatives and their therapeutic applications: a patent review (2009–2016)

Introduction: The benzopyran derivatives present a wide variety of biological activity and behaviour. At the same time the benzopyran derivatives support 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: This review summarizes new patents published on new benzopyran derivatives from 2009 to 2016.

Expert opinion: Many benzopyran derivatives have vivo/vitro biological responses. Their clinical evaluation will be critical to assess therapeutic utility. The compounds containing benzopyran moiety is well defined as lead compounds for design of new more promising molecules.     

Therapeutic potential of boswellic acids: a patent review (1990-2015)

Introduction: Boswellic acids (BAs), a group of pentacyclic triterpenoids, have demonstrated very interesting biological properties that resulted in a number of protocols being developed for their synthesis. During the last twenty-five years (1990–2015), numerous BAs have been prepared. Both natural BAs and their synthetic derivatives can be used to treat various cancers as well as inflammatory diseases.

Areas covered: This review covers patents on therapeutic activities of natural BAs and their synthetic derivatives published in last twenty-five years (1990–2015). Only BA patents to treat cancer and inflammation are available. A discussion about structure-activity relationships (SAR) of these analogs is also included.

Expert opinion: BAs possess excellent anticancer and anti-inflammatory properties. A large number of BAs and their analogues have been prepared through modification at the C₃-OH and C₂₄-CO₂H functional groups. Most importantly, the C-24 amide and amino derivatives demonstrated increased anticancer and anti-inflammatory activity compared with other BA derivatives. Furthermore, BAs have the potential to form conjugates with other anticancer drugs that will synergistically enhance their anticancer effects; and we believe that in order to get lead compounds, there needs to be a greater focus on the synthesis of halo derivatives of BAs.     

Taurine reduces blue light-induced retinal neuronal cell apoptosis in vitro

Background: The massive uptake of organic compatible osmolytes is a self-protective response to multiple stressors.

Objective: This study aimed to determine the protective effects of the osmolyte taurine against blue light-induced apoptosis in retinal neuronal cells in vitro.

Methods: Real-time PCR was used to measure osmolyte transport. Radioimmunoassays were performed to measure osmolyte uptake. Cell Counting Kit-8 assays were conducted to measure cellular viability. Flow cytometry analysis was used to measure apoptosis.

Results: Compared with normotonic stress, hypertonic stress-induced uptake of osmolytes, including betaine, myoinositol, and taurine, into the retinal neuronal cells. Blue light increased osmolyte transporter mRNA expression together with osmolyte uptake. Furthermore, taurine significantly suppressed blue light-induced retinal neuronal cell apoptosis.

Conclusion: The compatible osmolyte taurine may have an important role in cell resistance to blue light and cell survival.     

A patent review of immunoproteasome inhibitors

Introduction: The ubiquitin–proteasome system is responsible for maintaining protein homeostasis and regulating a variety of cellular processes. The constitutive proteasome is expressed in all cells while the immunoproteasome (IP) is predominantly found in cells of hematopoietic origin. In other cells, the expression of IP can be induced under the influence of cytokines released by T cells during acute immune and stress responses. Inhibitors of IP are of significant interest, because it is expected that selective inhibition of the IP would cause fewer adverse effects.

Areas covered: There is a considerable interest on patenting IP-specific inhibitors. Relevant patents and patent applications disclosing IP inhibitors are summarized and divided into two parts according to the chemical characteristics of compounds. We also briefly report on the biochemical methods used in the patents to profile the characteristics of IP inhibitors.

Expert opinion: Several selective inhibitors of IP with a promising ability to address autoimmune and inflammatory diseases are being developed. Peptidic compounds are prevalent and the most advanced IP-selective compounds to date, ONX-0914 and KZR-616, are tripeptide epoxyketone-based molecules. However, some patents disclose that IP-selective inhibition is possible with compounds possessing non-peptidic scaffolds indicating countless possibilities to address inhibition of IP in the future.     

Usnic acid and its derivatives for pharmaceutical use: a patent review (2000–2017)

Introduction: Usnic acid (UA) is a lichen-derived secondary metabolite with a unique dibenzofuran skeleton and is commonly found in lichenized fungi of the genera Usnea and Cladonia. Usnic acid has been incorporated for years in cosmetics, perfumery, and traditional medicines. It has a wide range of bioactivities, including antimicrobial, antiviral, anticancer, anti-inflammatory properties.

Areas covered: This review covers patents on therapeutic activities of UA and its synthetic derivatives published during the period 2000–2017.

Expert opinion: UA demonstrates excellent anticancer and antimicrobial properties. However, its application was withdrawn due to acute liver toxicity reported with chronic consumption. The broad spectrum of its biological activity indicates high the variability of UA’s binding preferences. The main idea to be addressed in the future should include the synthesis of UA derivatives because these might possess increased bioactivity, bioavailability and decreased toxicity. It is noteworthy that UA derivatives possessed better antibacterial, antitubercular, and anticancer activity than the parent compound . Most importantly, UA and its analogs (to a greater extent than UA) can be useful in cancer drug treatment. They have the potential for joint application with other anticancer drugs in order to overcome drug resistance.     

What’s new in treatment of pancreatic cancer: a patent review (2010–2017)

Introduction: Pancreatic cancer (PC) is one of the most lethal cancers, with a median overall survival of less than 1 year and a 5-year survival of ~5%. The poor survival rate is likely due to lack of early diagnosis, fast disease course, high metastasis rate and disappointing treatment outcome. Therefore, at this stage, any new method that provides a treatment against PC without the undesirable side effects of chemotherapy and radiation is urgently needed.

Areas covered: This review summarizes the latest advances in the treatment of PC through the patents published from 2010 to 2017. The patents reviewed include both new combinations of existing drugs and novel structures. New targets are proposed for developing new drugs.

Expert opinion: The patents reviewed entail different approaches which, on the one hand, improve the administration of existing drugs and therapies and, on the other, develop new drugs to act on novel targets. However, most of the new methods are in the first stage of development and need to be tested in vivo, in pre-clinical approaches and in clinical trials. Therefore, further assays will help confirm the activity, mechanisms of action, drug-drug interactions and other aspects that make a compound a good antitumoral agent.     

Safety of monoclonal antibodies for the treatment of multiple sclerosis

Introduction: Monoclonal antibodies are a potent therapeutic approach for relapsing-remitting multiple sclerosis. This group of medications comprises diverse mechanisms of action resulting in both shared and unique adverse effects.

Areas covered: The major trials and safety profiles of natalizumab, alemtuzumab, daclizumab, rituximab, and ocrelizumab are discussed. While each drug has a unique safety profile, one of the potential safety concerns for all of these drugs is infection, including for some progressive multifocal leukoencephalopathy. Other potential side effects and required monitoring for each drug are addressed.

Expert opinion: The treatment of multiple sclerosis is a balance between efficacy and safety. As a group, these medications are highly effective, but not without notable safety concerns; therefore more research is needed to understand the place these medications hold in the overall treatment algorithm.     

QSAR modelling: a therapeutic patent review 2010-present

Introduction: Quantitative Structure-Activity Relationship (QSAR) models are becoming one of the most interesting fields for developing therapeutics and therapeutics related patents. At present, QSAR methodologies comprise a series of possibilities, including joining forces with machine learning methods and increasing even more the swiftness they might bring to the prospective development of therapeutics in the Health Sciences scope.

Areas covered: After evaluating the period from 2010 to early 2018, the areas covered by the reviewed QSAR based therapeutics patents comprise three main fields (drug development, risk assessment and novel QSAR methodologies), and several areas, from cancer and cancer related symptomatology to neurodegenerative diseases, such as Parkinson’s disease, or even monitoring several chemical particles carrier-mediums or interface frontiers.

Expert opinion: Among the several conclusions drawn from this reviewing, some pertain to the near future of investigative research on QSAR based inventions for therapeutic purposes, while others include the prospective of an even more grown interest on cytotoxicity assessment with in silico models and protocols. Further, the type of compounds described in these types of patents is likely to see an increase in neurodegenerative diseases therapeutics, as the novel methodologies meet the challenging global health needs as human life expectancy increases.     

Taurine prevents ultraviolet B induced apoptosis in retinal ganglion cells

Background: Compatible osmolytes accumulation is an active resistance response in retina under ultraviolet (UV) radiation and hypertonicity conditions.

Objective: The purpose of this research is to investigate the protective role of taurine on retina under UVB radiation.

Methods: Osmolytes transporters were measured by quantitative realtime PCR. Osmolytes uptake was estimated by radioimmunoassay. Cell viability was calculated by MTT assay. Cell apoptosis was measured by flow cytometry analysis.

Results: Hypertonicity accelerated osmolytes uptake into retinal ganglion cells (RGCs) including taurine, betadine, and myoinositol. UVB radiation increased osmolytes transporter expression and osmolytes uptake. In addition, osmolyte taurine remarkably prevented UVB radiation induced cell apoptosis in RGCs.

Conclusions: The effect of compatible osmolyte taurine on cell survival rate may play an important role in cell resistance and adaption to UVB exposure.     

Quinazoline and quinazolinone as important medicinal scaffolds: a comparative patent review (2011–2016)

Introduction: Quinazoline and quinazolinone scaffolds represent an important class of biologically active nitrogen heterocyclic compounds. A variety of marketed drugs are based on these moieties. A diverse range of molecules with quinazoline/quinazolinone moieties have been reported to exhibit broad spectrum of biological activities.

Area covered: This review covers recent efforts in the synthesis and biological screening of quinazoline/quinazolinone based compounds from 2011–2016.

Expert opinion: Quinazoline and quinazolinones represent a diverse class of biologically active nitrogen heterocyclic compounds with immense therapeutic potential. Their ease of synthetic accessibility, and flexibility in structural modifications and functionalization further adds to their appeal in medicinal chemistry. A number of currently available drugs are based on quinazoline/quinazolinone scaffold. It is interesting to note that, among the recent patents available, a lot of them focus on the promising anticancer activity of quinazoline and quinazolinone containing compounds. However their biological activity is certainly not limited to anticancer only, they are also known to elicit a number of other biological and physiological effects in vitro and in vivo respectively. The interest in quinazolines and quinazolinones is ever growing, since they offer a fairly diverse chemical space for exploration of medicinal potential.     

Olaparib for the treatment of breast cancer

Introduction: Basal-like breast cancer is characterized by being triple negative and aggressive. Defects in DNA repair is a promising therapeutic target as BRCA alterations are found in 11 to 42% of these tumors, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors exploit this deficiency through a synthetic lethality and are considered as promising anticancer therapies, especially in patients harboring BRCA1 or BRCA 2 mutations.

Areas covered: Olaparib is one of the most widely investigated PARP inhibitors. Here, the preclinical data, completed clinical trials and ongoing investigations are discussed.

Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance. Moreover, the results from ongoing phase III trials of olaparib in breast cancer are still awaited.     

A comparative safety review between GLP-1 receptor agonists and SGLT2 inhibitors for diabetes treatment

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose cotransporter 2 inhibitors (SGLT2i) are of particular interest in type 2 diabetes treatment strategies, due to their efficacy in reducing HbA1c with a low risk of hypoglycaemia, to their positive effects on body weight and blood pressure and in light of their effects on cardiovascular risk and on nephroprotection emerged from the most recent cardiovascular outcome trials.

Since it is therefore very likely that GLP-1RA and SGLT2i use will become more and more common, it is more and more important to gather and discuss information about their safety profile.

Area Covered: adverse events and the safety concerns most often emerged in trials with GLP-1RA namely, exenatide long acting release (LAR), dulaglutide, liraglutide, semaglutide, lixisenatide or SGLT2i, namely empagliflozin, dapagliflozin, canagliflozin and SGLT2i with an attempt at comparing the safety profiles of molecules of these two classes.

Expert opinion: GLP-1RA and SGLT2i, although each associated with different specific side effects, share a ‘similar’ safety profile and are both drugs relatively easy to handle. The potentially complementary mechanisms of action, the cardio and nephroprotective effects demonstrated by molecules of both classes, make these drugs potentially useful even in add on to each other.     

Melphalan hydrochloride for the treatment of multiple myeloma

Introduction: Multiple myeloma (MM) is an incurable disease characterized by clonal plasma cell proliferation and overproduction of monoclonal paraprotein, hypercalcemia, renal failure, anemia, osteolytic bone lesions, and infections.

Melphalan, a nitrogen mustard, is an alkylating agent synthesized in 1953, and it has been used in multiple myeloma therapy for fifty years. Although novel agents have been introduced in the past few decades improving prognosis of the disease, melphalan still maintains a crucial role in the treatment of MM acting both as cytotoxic agent through damage to DNA, and as immunostimulatory drug by inhibiting Interleukin-6, as well as interaction with dendritic cells, and immunogenic effects in tumor microenvironment.

Areas covered: This review focuses on available data about melphalan pharmacology and its role in clinical practice.

Expert opinion: Melphalan remains crucial in therapy of multiple myeloma because of its good manageability, safety profile, efficacy, and economic sustainability. These characteristics make it pivotal also for new regimens in combination with novel agents.     

A review on phytochemical and pharmacological properties of Litsea coreana

Context: Litsea coreana H. Lév. (Lauraceae) is used as an ethnic herb or beverage in China. Substantial studies indicate that it contains a variety of compounds and shows diverse bioactivities with no toxicity.

Objective: This review analyzes and summarizes the ethnopharmacological applications, phytochemistry, and pharmacological activities and molecular mechanisms of L. coreana.

Methods: Related literature (from 1998 to 2016) was obtained and compiled via searching databases including Scopus, Web of Science, Google Scholar, CNKI and PubMed. Keywords (Litsea coreana, hawk tea, eagle tea and laoying cha) were used to select the articles.

Results: Studies indicate that L. coreana contains characteristic polysaccharides, polyphenols, essential oils, and numerious flavonoids, which exhibit remarkable bioactivities, such as hepatoprotection, hyperglycaemia, anti-inflammation, antioxidation and antibacterial, through multiple molecular mechanisms.

Conclusion: This paper provides a systematic review on the phytochemicals and pharmacological activities of L. coreana which should be useful for further study and application of this medicinal herb.     

Tetrahydroisoquinolines in therapeutics: a patent review (2010-2015)

Introduction: 1,2,3,4-Tetrahydroisoquinoline (THIQ) is one of the ‘privileged scaffolds’, commonly found in nature. Initially, this class of compounds was known for its neurotoxicity. Later on, 1-methyl-1,2,3,4-tetrahydroisoquinoline was proved as an endogeneous Parkinsonism-preventing agent in mammals. The fused THIQs have been studied for their role as anticancer antibiotics. The US FDA approval of the trabectedin for the treatment of soft tissue sarcomas, is a milestone in the anticancer drug discovery.

Areas covered: This review covers the patents on various therapeutic activities of the THIQ derivatives in the years between 2010 and 2015. Patents were collected using a thorough search of Espacenet and WIPO databases. The therapeutic areas covered include cancer, malaria, central nervous system (CNS), cardiovascular, metabolic disorders, and so on. This also includes several patents on specific THIQs of clinical importance.

Expert opinion: A large number of the THIQ derivatives have been synthesised for various therapeutic activities, with noticeable success in the area of drug discovery for cancer and CNS. They may also prove to be promising candidates for various infectious diseases, such as malaria, tuberculosis, HIV-infection, HSV-infection, leishmaniasis, etc. They can also be developed as novel class of drugs for various therapeutic activities with unique mechanism of action.     

Saffron and its derivatives,crocin, crocetin and safranal: a patent review

Introduction: Saffron and its main components have traditionally been used as pharmaceutical agents. Current experimental research projects have also exhibited their applications in a wide spectrum of disorder treatments.

Area covered: This review covers the demonstrated findings and patents on therapeutic/pharmaceutical properties of saffron and related derivatives, since 2000 to bold their outstanding merit on human health. An extensive literature review was performed in USP Patent, Patentscope, Espacenet and Google Patent in the field of CNS, cardiovascular, urogenital, dermatological and inflammatory disorders.

Expert opinion: The growing body of patents showed the value of saffron and the respective crucial components alone or in combination with the other raw materials, herbal extracts, to apply in various therapeutic/pharmaceutical areas. They could be engaged as an adjuvant treatment in phototherapy, cancer, cardiovascular and neurodegenerative diseases and hypoxia-induced dangerous conditions. However, the application of these components in the clinic has been limited to very few drugs yet. This might be due poor clinical trials data. According the human trend toward the use of plant-derived compounds instead of medicines derived from chemical substances, special attention must be focused to link the worth of saffron, herbal medicine of third millennium, from basic sciences to patients’ bed.     

Inhibitors of α-glucosidase and α-amylase from Cyperus rotundus

Context: A methanol extract of Cyperus rotundus L. (Cyperaceae) rhizomes showed inhibitory activity against α-glucosidase and α-amylase, two enzymes involve in carbohydrate digestion.

Objective: Identification of compounds from C. rotundus rhizomes responsible for the inhibition of α-glucosidase and α-amylase.

Materials and methods: Compounds were identified by a phytochemical investigation using combined chromatographic and spectroscopic methods. α-glucosidase and α-amylase inhibitory activities were evaluated by in vitro enzyme inhibition assays.

Results: A new (2RS,3SR)-3,4′,5,6,7,8-hexahydroxyflavane (1), together with three known stilbene dimers cassigarol E (2), scirpusin A (3) and B (4) were isolated. Compound 2 inhibited both α-glucosidase and α-amylase activities while the flavane 1 only showed effect on α-amylase, and compounds 3 and 4 were active on α-glucosidase. All four compounds showed significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity.

Discussion: The inhibitory activities against α-amylase and α-glucosidase of the C. rotundus rhizomes were reported for the first time. Stilbene dimers are considered as potent inhibitors of α-glucosidase and promising antihyperglycemic agents.

Conclusion: The isolated compounds may contribute to the antidiabetic property of C. rotundus.