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.     

Resveratrol derivatives: a patent review (2009 – 2012)

Introduction: There is currently a wealth of information on the effects of resveratrol and its derivatives in therapeutic, cosmetic and nutraceutical patent applications. Structure–activity studies of the resveratrol scaffold provide a foundation for the development of new analogs with potent activity or other beneficial properties. Ongoing research has yielded promising results and potential use in the treatment of various diseases.

Areas covered: This review provides analysis of patents published from January 2009 to April 2013. There is a focus on different approaches for the production of resveratrol derivatives, combinations of new derivatives with old drugs, and applications in therapeutic areas, nutraceutical compositions and cosmetics.

Expert opinion: The ability of resveratrol to interact with a disparate array of subcellular targets is uncanny. Nonetheless, even though limited or no toxicity is apparent, the molecule is not a panacea due to lack of potency and issues with bioavailability. Thus, as witnessed by a number of patents, a large assortment of derivatives have been synthesized under the guise of having superior characteristics for treating or preventing various diseases or for use as neutraceutics and cosmetics. Some of these suppositions are probably correct, but evidence-based applications are essentially nil due to a lack of commitment in terms of investing the resources necessary for the conduct of obligatory clinical trials. Current usage is largely based on anecdotes and publicity. Hopefully, at some point in time, it will be possible to follow a standard protocol with a predicable outcome.     

Artemisinin derivatives: a patent review (2006 – present)

Introduction: The isolation of artemisinin from an ancient Chinese remedy in the early 1970s heralded the beginning of a new era in antimalarial drug therapy culminating in artemisinin-based combination therapies currently being the mainstay of malaria treatment worldwide. Ongoing research on this compound and its derivatives has revealed its potential use in treating other infectious and noninfectious diseases.

Areas covered: This review provides a summary of patents published globally from January 2006 to June 2012 covering promising artemisinin derivatives and artemisinin-based drug combinations developed for use in various therapeutic areas.

Expert opinion: The diversity of semi-synthetic artemisinin derivatives has been limited to the same design strategy of modifying the artemisinin molecule at the same positions due to inherent synthetic challenges. To address this, future endeavors should include: the use of biotransformation strategies to modify other positions in the sesquiterpene ring while retaining the endoperoxide bridge; the design and synthesis of synthetic ozonides based on the pharmacophoric endoperoxide motif and drug repositioning approaches to artemisinin-based combination therapy. A better understanding of the mechanism of action of artemisinin derivatives and their biomolecular targets may provide an invaluable tool for the development of derivatives with a wider array of activity and greater clinical utility than currently appreciated.     

Imidazoline derivatives: a patent review (2006 – present)

Introduction: Recent decades have witnessed the growing interest in the development of imidazoline derivatives in drug discovery due to increased knowledge in pathogenesis of many diseases. Imidazoline structure has been one of the most sought-after scaffolds employed in developing various agents with different kinds of pharmacological activities. During 2006 – 2012, imidazoline structures have been found in numerous patented compounds for the treatment of neurodegenerative diseases and cancer.

Areas covered: This paper provides a general review of patented imidazoline derivatives from 2006 to 2012. Information from articles published in international peer-reviewed journals has also been included to give a more exhaustive overview.

Expert opinion: With the uncovering of the molecular mechanisms related to neurodegenerative diseases and cancer, the use of classical and novel imidazoline structures has been more frequently noted in recent (2006 – 2012) patented agents for the treatment of neurodegenerative diseases and cancer instead of agents for the treatment of cardiovascular disease noticed earlier.     

Glycine transporter-1 inhibitors: a patent review (2011–2016)

Introduction: Numerous research groups have developed GlyT-1 inhibitors in the pursuit of providing a novel antipsychotic treatment for schizophrenia. Despite multiple compounds advancing into clinical trials, a GlyT-1 inhibitor has yet to emerge to treat patients. However, the approach remains heavily investigated as it presents potential therapeutic utility for several other CNS and non-CNS-related indications.

Areas covered: This review discusses various GlyT-1 inhibitor chemotypes identified and provides an overview of patent applications filed and published during the period of 2011–2016. The review largely focuses on composition of matter patent applications, although two recently disclosed method of use patents are discussed. Clinical reports are also disseminated.

Expert opinion: Mounting clinical failures with schizophrenic patients have blunted enthusiasm for GlyT-1 inhibition as an approach to treat the disease. However, research in the area remains quite active, as therapeutic potential for several additional indications has emerged. There are numerous and diverse GlyT-1 chemotypes now available that exhibit differentiating modes of binding and ligand-target binding kinetics, and this rich diversity of chemical matter may help further elucidate the target’s pharmacological role in various indications and lead to the identification of a compound with optimal properties that may someday become a drug.     

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.     

Betulinic acid and its derivatives: a patent review (2008 – 2013)

Introduction: Betulinic acid (BA) is a triterpenoid that can be obtained from renewable resources. BA is cytotoxic to many human tumor cell lines mainly by apoptosis but cell death might also be triggered by nonapoptotic pathways. Many derivatives have been synthesized to improve the very weak solubility of parent BA and to increase its cytotoxicity as well as its selectivity toward tumor cells.

Areas covered: A brief introduction into cancer is given reflecting the different pathways this disease might be treated using chemotherapy using natural product analogs especially triterpenes. The different ways of action of BA in cancer cells are discussed. Finally, this review describes the main synthetic modifications that have been performed and discusses, in short, the structure–activity relationships of these analogs, investigated between 2008 and 2013 including some important publications from early 2014.

Expert opinion: A number of patents on BA analogs for the chemotherapy of cancer have been reported between 2008 and 2013. Most of these patents deal with modifications at positions C-3, C-20 and C-28. There are only a few compounds meeting the needs of a sufficient hydrosolubility, while retaining high cytotoxicity and selectivity toward tumor cells. Thus, one might expect that there will be some efforts in developing molecules of improved solubility and to find new and more efficient forms of administration (liposomes, transdermal application and nanoemulsions). An important sideline might be the treatment of the age-dependent degeneration of the macula, a possible caveat of which might be a certain degree of CNS toxicity associated with several derivatives of BA.     

5-Fluorouracil derivatives: a patent review (2012 – 2014)

Introduction: 5-Fluorouracil (5-FU)-based chemotherapy is the most widely prescribed treatment for gastrointestinal solid tumors, but there are several drawbacks such as toxicities, lack of selectivity and effectiveness as well as the development of resistance that need to be overcome.

Areas covered:In this review, the authors present the latest innovations in 5-FU derivatives or combinations with: i) other chemotherapeutic drugs; ii) novel targeted compounds; iii) radiotherapy; iv) mAbs; v) siRNA strategies; and vi) traditional Chinese medicine extracts. Moreover, advances to overcome or determine 5-FU adverse effects and effectiveness are described. Finally, the authors introduce the ongoing clinical trials and highlight the main challenges to be addressed in the future.

Expert opinion: Although in the past few years there has been a great advancement in the antitumor effectiveness and selectivity of 5-FU-based therapies, it is envisaged that future approaches using ‘omics’ technologies that could determine the tumor heterogeneity may help in identifying additional candidate genes, microRNAs or cytokines involved in both the path mechanisms of 5-FU-related toxicity and its therapeutic efficacy. Moreover, the development of novel targeted 5-FU derivatives or 5-FU-based therapies tailored to individual patients opens up new possibilities in the improvement of the quality of life and survival for those suffering from this devastating disease.     

Vitamin E derivatives: a patent review (2010 – 2015)

Introduction: The vitamin E family consists of four tocopherols and four tocotrienols. α-Tocopherol is the most studied member of this family for its antioxidant and non-antioxidant properties, while tocotrienols have attracted recent research interest. The structural motifs of the vitamin E family and specifically the chroman moiety, are amenable to various modifications in order to improve their bioactivities towards numerous therapeutic targets.

Areas covered: This review includes the patent literature from 2010 – 2015 related to vitamin E derivatives and it is focused on 2-, 5- or 6-substituted chroman analogues. The patent search was performed using Reaxys® and esp@cenet.

Expert opinion: The chroman moiety of vitamin E is a privileged structure and an essential pharmacophore which inspired organic chemists to synthesize new analogues with improved bioactivities. Modifications at the 2- and 5- positions of the chroman ring resulted in very interesting active compounds in cellular and animal models of diseases related to oxidative stress. More recent publications and patents reported 6-substituted chromans as anticancer agents in vitro and in vivo. Additionally, an emerging interest is observed towards the use of vitamin E analogues incorporated in drug delivery systems and for medical imaging as contrast agents or fluorescent probes.     

Novel urate transporter 1 (URAT1) inhibitors: a review of recent patent literature (2016–2019)

ABSTRACT

Introduction: Human urate transporter 1 (URAT1), which is an influx transporter protein, is located at the apical surface of renal tubular cells and presumed to be the major transporter responsible for the reabsorption of urate from blood. About 90% of patients develop hyperuricemia due to insuf?cient urate excretion; thus, it is important to develop URAT1 inhibitors that could enhance renal urate excretion by blocking the reabsorption of urate anion.

Areas covered: In this review, the authors addressed the patent applications (2016–2019) about URAT1 inhibitors and some medicinal chemistry strategies employed in these patents.

Expert opinion: Substituent decorating, bioisosterism, and scaffold hopping are three common medicinal chemistry strategies used in the discovery of URAT1 inhibitors. Meanwhile, the introduction of sulfonyl group into small molecules has become one of the important strategies for structural optimization of URAT1 inhibitors. Furthermore, developing drug candidates targeting both URAT1 and xanthine oxidase (XOD) has attracted lots of interest and attention.     

Novel diagnostic tools and solutions for multiple sclerosis treatment: a patent review (2009 – 2014)

Introduction: With > 2 million people affected by multiple sclerosis (MS) worldwide, the elucidation of its etiopathogenesis is of highest interest. Ongoing research in medicine, molecular biology, chemistry and physics aims to improve the life of MS patients by increasing efficacy and decreasing adverse side effects of presently available drugs. A precise diagnosis of this complex disease, which can take different courses, is fundamental to finding an efficient treatment strategy.

Areas covered: We present a summary of diagnostic and therapeutic patents granted between 2009 and 2014. Diagnostic inventions use both genetic and proteomic approaches or measure cerebral venous hemodynamics. Instead, new treatments rely on small molecules and/or the active manipulation of proteins that are involved in the pathogenesis of MS.

Expert opinion: There are some promising approaches among recently published patents. In particular, genetic profiling for diagnosis, combination of novel drugs with FDA-approved drugs to reduce side effects, and the personalisation of MS treatments according to a more defined diagnosis are considered as important. In the light of the latest developments, we discuss the complex picture of MS, which we assume to be different events connected by a causal chain consisting of circulatory abnormalities, altered redox processes in CNS immune cells, oligodendropathy, inflammation and finally autoimmunity.     

Novel antifungal agents: a patent review (2011 – present)

Introduction: Invasive fungal infections (IFI) have increased significantly over the past decades. The mortality rate of IFI is alarming, and early and accurate diagnosis is difficult. Most used antifungal drugs are not completely effective due to the development of increasing resistance and undesirable side effects which limit their use. In this scenario, new effective broad spectrum and safer antifungal drugs are urgently needed.

Areas covered: This review summarizes the latest advances in the discovery of new antifungal compounds through the patents granted from 2011 to August 2013. In the 26 patents reviewed here, either derivatives of existing antifungal drugs or novel structures are included. New imidazoles, fluconazole analogs and adducts of azoles with 2,6-di-tert-butyl-4-methylphenol are described. The review also includes chitinases, β-1,3-D-glucan and chitin synthases inhibitors and novel structures.

Expert opinion: In the patents reviewed here, progress has been made to accomplish at least one of the necessary requirements for the development of novel antifungal agents, such as broad spectrum of activity, more favorable pharmacokinetic profile, good bioavailability and low adverse effects. However, in vivo activity, mechanisms of action, drug–drug interactions and other aspects that make a compound a good antifungal agent need further development.     

Novel FabH inhibitors: a patent and article literature review (2000 – 2012)

Introduction: The traditional antimicrobial chemotherapy drugs play their effects mostly via bacterial interference with in vivo amino acids, nucleotides, amino sugars and other small molecule synthesis, or interfering the biochemical processes of these small molecules to synthesize nucleic acids, peptidoglycan and other biological macromolecules. In recent years, enzymes with single function in bacterial fatty acid synthetase system have become the genome-driven novel antibacterial drug targets. Among inhibitors of these targets, FabH inhibitors are distinguished, for their target is different from that of existing antibiotics. Therefore, discovery of FabH inhibitors might be a potential orientation to overcome bacterial resistance.

Areas covered: This review summarized new patents and articles published on FabH inhibitors from 2000 to 2012.

Expert opinion: The review gives a brief understanding about the background and development in the area of FabH inhibitors that aims to solve the bacterial resistance problem. This review puts emphasis on some typical small molecules, which participate in the process of FabH inhibition. Overall, the research scopes of antibacterial agents are getting broad. Fatty acid synthase (FAS) pathway has been proved to be a promising target for the therapy. However, claim of novel antibacterial agents with more active and higher specificity is still continued.     

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.     

New substituted benzimidazole derivatives: a patent review (2013 – 2014)

Introduction: The benzimidazole nucleus is found in a variety of naturally occurring compounds and is of significant importance in medicinal chemistry. Owing to its conspicuous pharmacological properties, benzimidazoles have become an important pharmacophore and sub-structure in drug design and have been screened for a wide range of biological activities.

Areas covered: Areas covered in this paper include a review of the biological effects, mechanisms and synthesis of benzimidazole derivatives in the past 2 years based on patents. The patent databases Scifinder and esp@cenet were used to locate patent applications that were published between 2013 to present. Information from articles published is also included.

Expert opinion: Benzimidazole derivatives are remarkably effective compounds to many diseases and may have the potential to be the first effective therapy against Ebola virus. Therefore, it is of great importance to develop specific design software and sustainable industrial synthetic routes for the development of effective and clinically relevant benzimidazole compounds.     

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.     

Novel monoamine oxidase inhibitors: a patent review (2012 – 2014)

Introduction: Monoamine oxidase (MAO) inhibitors, despite the initial pharmacological interest, are used in clinic for their antidepressant effect and in the management of Parkinson symptoms, due to the established neuroprotective action. Efficacy and tolerability emerged from large-scale and randomized clinical trials.

Areas covered: Thirty-six patents range from April 2012 to September 2014. The number of chemotypes with inhibitory effects on MAO is truly high (40 synthetic compounds, 22 natural products and 6 plant extracts reported and licensed), and the present review is comprehensive of all compounds, which have been patented for their relevance to clinical medicine in this period range (27 patents). Moreover, some of the collected patents deal with new formulations of compounds endowed with MAO inhibitory properties (two patents) and new therapeutic options/drug associations for already known MAO inhibitors (seven patents).

Expert opinion: The patents reported in this review showed that the interest in this field is constant and mainly devoted to the study of selective MAO-B inhibitors, used as drugs for the treatment of neurological disorders. The development of novel human MAO inhibitors took advantage of the discovery of new therapeutic targets (cancer, hair loss, muscle dystrophies, cocaine addiction and inflammation), the recognized role of MAOs as molecular biomarkers and their activity in other tissues.     

Rho kinase inhibitors: a patent review (2014 – 2016)

Introduction: The Rho-kinases (ROCK), ROCK1 and ROCK2, are potent, widespread biochemical modulators which have been extensively studied. Due to the involvement of ROCKs in multiple biological processes, ROCK inhibitors have pleiotropic actions and may be of relevance for a number of therapeutic applications. The drawback is however that their use might be limited by occurrence of side effects.

Areas covered: Since the publication of the latest review in 2014, there have been significant advances in the field of ROCK inhibitors. In this paper we reviewed the patents published between September 2013 and September 2016. Recent novel molecules will be described. and progress from the compounds series described in the previous review as well as any new expected therapeutic uses for ROCK inhibitors that popped up in the last three years will be examined.

Expert opinion: While a number of potential applications in human for ROCK inhibitors have been reported, very few molecules are currently available to patients. In addition to fasudil, ripasudil (K-115, Kowa) was only recently approved in Japan for the treatment of glaucoma (2014). Notwithstanding some failures and subsequent discontinuation, the Pipeline of preclinical and clinical ROCK inhibitors remains significant.     

Treatments and compositions targeting α-synuclein: a patent review (2010-2016)

Introduction: Abnormal deposition of α-synuclein (ASN) is a hallmark and possible central mechanism of Parkinson’s disease and other synucleinopathies. Their therapy is currently hampered by the lack of early, screening-compatible diagnostic methods and efficient treatments.

Areas covered: Patent applications related to synucleinopathies obtained from Patentscope and Espacenet databases are described against the background of current knowledge regarding the regulatory mechanisms of ASN behavior including alternative splicing, post-translational modifications, molecular interactions, aggregation, degradation, and changes in localization.

Expert opinion: As the central pathological feature and possibly one of root causes in a number of neurodegenerative diseases, deregulation of ASN is a potentially optimal diagnostic and therapeutic target. Changes in total ASN may have diagnostic value, especially if non-invasive /peripheral tissue tests can be developed. Targeting the whole ASN pool for therapeutic purposes may be problematic, however. ASN mutations, truncation, and post-translational modifications have great potential value; therapeutic approaches selective towards aggregated or aggregation-prone ASN forms may lead to more successful and safe treatments. Numerous ASN interactions with signaling pathways, protein degradation and stress mechanisms widen its potential therapeutic significance dramatically. However, significant improvement in the basic knowledge on ASN is necessary to fully exploit these opportunities.