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.     

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.     

Quinazoline derivatives as potential anticancer agents: a patent review (2007 – 2010)

Introduction : Due to the increase in knowledge about cancer pathways, there is a growing interest in finding novel potential drugs. Quinazoline is one of the most widespread scaffolds amongst bioactive compounds. A number of patents and papers appear in the literature regarding the discovery and development of novel promising quinazoline compounds for cancer chemotherapy. Although there is a progressive decrease in the number of patents filed, there is an increasing number of biochemical targets for quinazoline compounds.

Areas covered : This paper provides a comprehensive review of the quinazolines patented in 2007 – 2010 as potential anticancer agents. Information from articles published in international peer-reviewed journals was also included, to give a more exhaustive overview.

Expert opinion : From about 1995 to 2006, the anticancer quinazolines panorama has been dominated by the 4-anilinoquinazolines as tyrosine kinase inhibitors. The extensive researches conducted in this period could have caused the progressive reduction in the ability to file novel patents as shown in the 2007 – 2010 period. However, the growing knowledge of cancer-related pathways has recently highlighted some novel potential targets for therapy, with quinazolines receiving increasing attention. This is well demonstrated by the number of different targets of the patents considered in this review. The structural heterogeneity in the patented compounds makes it difficult to derive general pharmacophores and make comparisons among claimed compounds. On the other hand, the identification of multi-target compounds seems a reliable goal. Thus, it is reasonable that quinazoline compounds will be studied and developed for multi-target therapies.     

Glycosidase inhibitors: a patent review (2008 – 2013)

Introduction: In the recent decades, the interest on glycosidases has dramatically increased, mainly because these enzymes play a key role in many biological processes. The importance of these enzymes is also reflected by a number of diseases, which result from the lack or dysfunction of a given glycosidase, as well as by the use of glycosidase inhibitors in the treatment of metabolic disorders or viral infections. Based on the biological potential associated to these enzymes, several glycosidase inhibitors have been developed. In this review, the most important inhibitors targeting these enzymes, including the disaccharides, iminosugars, carbasugars, thiosugars and other non-glycosidic compounds will be discussed and special attention will be given to the ones that are currently used clinically.

Areas covered: This review summarizes and characterizes the current knowledge regarding the classes of glycosidase inhibitors that have therapeutic potential in a wide range of diseases. It highlights the relevant research, patents and patent applications filed in the past years on the field.

Expert opinion: Since the glycosidase inhibitors are involved in several chronic diseases and possibly pandemic, the pharmaceutical research toward developing new generations of these molecules is very important to public health in the world. The unique combination of these compounds – for example, they share many properties with natural carbohydrates and also possess distinct specific characteristics – makes them precious for pharmaceutical companies in an attempt to search for potential new drugs. Currently, the most promising compounds are the iminosugars and thiosugars due to their better oral bioavailability.     

Chloroquine-containing compounds: a patent review (2010 – 2014)

Introduction: Chloroquine (CQ) has been well known for its antimalarial effects since World War II. However, it is gradually being phased out from clinical use against malaria due to emergence of CQ-resistant Plasmodium falciparum strains. Besides low cost and tolerability, ongoing research has revealed interesting biochemical properties of CQ that have inspired its repurposing/repositioning in the management of various infectious/noninfectious diseases. Consequently, several novel compounds and compositions based on its scaffold have been studied and patented.

Areas covered: In this review, patents describing CQ and its derivatives/compositions over the last 5 years are analyzed. The review highlights the rationale, chemical structures, biological evaluation and potential therapeutic application of CQ, its derivatives and compositions.

Expert opinion: Repurposing efforts have dominantly focused on racemic CQ with no studies exploring the effect of the (R) and (S) enantiomers, which might potentially have additional benefits in other diseases. Additionally, evaluating other similarly acting antimalarials in clinical use and structural analogs could help maximize the intrinsic value of the 4-aminoquinolines. With regard to cancer therapy, successful repurposing of CQ-containing compounds will require linking the mode of action of these antimalarials with the signaling pathways that drive cancer cell proliferation to facilitate the development of a 4-amino-7-chloroquinoline that can be used as a synergistic partner in anticancer combination chemotherapy.     

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.     

β-Lactamase inhibitors: a review of the patent literature (2010 – 2013)

Introduction: New β-lactamases with ever-broadening substrate specificity are rapidly disseminating globally, thereby threatening the efficacy of our best β-lactam antibiotics. A potential solution to this problem is the development of wide-spectrum β-lactamase inhibitors, to be coadministered with existing and new β-lactams.

Areas covered: This review covers the patent literature in the β-lactamase inhibitor area roughly from 2010 to 2013, with prior background being provided in the cases of key inhibitors and antibiotic/inhibitor combinations. An effort has been made to identify the strong and weak points of each inhibitor and combination.

Expert opinion: Research in this field has become increasingly diverse, with several non-β-lactam inhibitor classes now assuming importance. The emphasis has been on finding inhibitors of AmpC, the extended-spectrum β-lactamases and class A and D carbapenemases that can demonstrate synergy with antibiotics against resistant Gram-negative pathogens. Progress has been made. Metallo-β-lactamases (MBL)-mediated resistance, however, represents an unmet challenge. The author believes that it will be extremely difficult to generate a selective, commercially viable MBL inhibitor with sufficient activity against NDM-1 and that alternate design strategies will need to be employed.     

Antiplasmodial drug targets: a patent review (2000 – 2013)

Introduction: New antimalarials with novel modes of action are crucial in countering the challenge of emerging drug-resistant Plasmodium falciparum. Equally significant is the identification and characterization of the targets these compounds inhibit. Biochemical evidence from seminal studies, whole genome clues and high-throughput chemical screening data provide starting points worth exploring in target identification efforts. Several proteins and biochemical processes/pathways critical to parasite survival have since been profiled and patented.

Areas covered: In this review, an analysis of patents describing the characterization of different enzymatic and/or biosynthetic targets in P. falciparum over the last fourteen years is presented. The review also details structures, biological evaluation, potential modes of action and therapeutic utilities of small molecule antiplasmodial compounds from ongoing research, designed to inhibit these targets.

Expert opinion: Though various strategies to address antimalarial drug resistance exist, direct inhibition of unrelated targets and non-genome coded processes potentially present the most effective options. Additionally, interest in peptides as antimalarials merits further exploration especially in view of their unique low susceptibility to resistance, wider spectrum of action and faster activity. Finally, target-based optimization and chemical validation of novel targets can be facilitated by routine phenotypic whole-cell screening of antiplasmodial hits against any new target(s).     

CXCR2 modulators: a patent review (2009 – 2013)

Introduction: Small-molecule antagonists of CXC chemokine receptor 2 (CXCR2) have attracted a considerable amount of attention due to the key central role that this receptor plays in inflammatory conditions. Recently, several CXCR2 receptor antagonists have demonstrated promising proof of activity in early pulmonary clinical trials, which has stimulated additional efforts to identify new CXCR2 receptor antagonists.

Areas covered: During the period 2009 – 2013, there were numerous patent publications from various companies claiming the discovery of novel CXCR2 receptor antagonists. Herein, an interpretation of these new patent publications combined with emerging disclosures from the peer-reviewed literature during this time frame is given. This review highlights the preferred or representative compounds from the patent applications along with relevant biological characterization.

Expert opinion: Many of the new CXCR2 receptor antagonists described in this review represent closely related analogs to previously disclosed clinical candidates. With the recent discontinuation of several CXCR2 receptor antagonists in the clinic, additional clinical trial information for CXCR2 receptor antagonists, both past and present, will determine the long-term therapeutic potential of these compounds for the treatment of a variety of inflammatory disorders.     

Matrix metalloproteinase inhibitors: a patent review (2011 – 2013)

Introduction: The MMPs are involved in tissue remodeling. An imbalance between the inhibition and activation of MMPs results in excessive degradation of the extracellular matrix, which leads to some diseases including cancer, rheumatoid arthritis, osteoarthritis, heart disease and neurodegenerative diseases such as stroke. In this review, recent advances in the research of MMP inhibitors are reviewed.

Areas covered: This updated review summarized new patents on MMP inhibitors within January 2011 – December 2013.

Expert opinion: This review gives the latest development in the area of MMP inhibitors, which aim to treat disease processes associated with the MMPs. Structure-based design techniques have been used successfully in the search of selective MMP inhibitors, and these inhibitors can also be derived from natural products. Furthermore, imaging ‘in vivo’ technologies have been developed in order to follow the drug distribution to the targeted tissues, and to quantify the drug efficiency.     

Drugs for dengue: a patent review (2010 – 2014)

Introduction: Almost half the global population is estimated to be at risk of contracting dengue infection. Of the 400 million infections estimated to occur annually, 4 million can be potentially life-threatening leading to vascular leakage and shock. The only treatment available to severe dengue patients is fluid replacement therapy and supportive care. A drug for treating dengue is an urgent need.

Areas covered: This article endeavors to provide an overview of the experimental dengue drugs being developed around the world as reflected in the recent patent literature spanning the last few years (2010 – 2014).

Expert opinion: Dengue drug development is essentially in its infancy and currently hobbled by multiple factors including a poor understanding of the molecular mechanism of severe disease and lack of reliable small animal model for preclinical drug evaluation. More intense R&D coupled to setting up product development partnerships to facilitate the efficient movement of a drug molecule from the laboratory to the clinic is needed to make antiviral therapy for dengue a reality in the coming future.     

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.     

Toll-like receptor modulators: a patent review (2006 – 2010)

Introduction: The immune response is mediated via two parallel immune components, innate and adaptive, whose effector functions are highly integrated and coordinated for the protection of the human body against invading pathogens and transformed cells. The discovery of pathogen recognition receptors (PRRs), most notably toll-like receptors (TLRs), in innate immunity has evoked increased interest in the therapeutic handling of the innate immune system. TLRs are germ line-encoded receptors that play a potent role in the recognition of a diverse variety of ligands ranging from hydrophilic nucleic acids to lipopolysaccharide (LPS) or peptidoglycan (PGN) structures in pathogens.

Areas covered: This review discusses recent updates (2006 – 2010) in completed, ongoing and planned clinical trials of TLR immunomodulator-based therapies for the treatment of infectious diseases, inflammatory disorders and cancer.

Expert opinion: Since the discovery of human TLRs, modulating immune responses using TLR agonists or antagonists for therapeutic purposes has provoked intense activity in the pharmaceutical industry. The ability of TLRs to initiate and propagate inflammation makes them attractive therapeutic targets. We are now at the stage of evaluating such molecules in human diseases. Additionally, there is also extensive literature available on TLRs in diseased states. These data provide a basis for the identification of novel immunomodulators (agonists and antagonists) for the therapeutic targeting of TLRs.     

Inducible tyrosine kinase inhibitors: a review of the patent literature (2010 – 2013)

Introduction: The non-receptor tyrosine kinase, inducible tyrosine kinase (Itk), plays an important role in thymus(T)-cell signalling and the production of pro-inflammatory cytokines. Itk, and the other Tec family members, Rlk and Tec, are viewed as attractive drug targets for new agents for the treatment of autoimmune and inflammatory diseases. Interest in Itk inhibitors is still modest compared to other kinases such as the Janus kinase (JAK) family or Syk.

Areas covered: This article reviews the patent filings published from January 2010 to April 2014 that claim Itk inhibitors. It first considers those applications that claim selective, or apparently selective, Itk inhibitors. It then considers those applications that claim less-selective Itk inhibitors. The recent interest in irreversible Itk inhibitors is also discussed.

Expert opinion: There is a difference of opinion as to the preferred utility for Itk inhibitors. Progress has been made in designing selective Itk inhibitors but little clinical progress. Until clinical data are available, it remains difficult to assess how well Itk inhibitors compare with JAK inhibitors as potential treatments for rheumatoid arthritis. However, animal data suggest that irreversible Itk inhibitors could be useful in treating asthma, whereas dual Itk inhibitors may have more utility in treating rheumatoid arthritis.     

Modulators of complement activation: a patent review (2008 – 2013)

Introduction: The architecture of the complement system has evolved during the last 600 – 700 million years to become an amazingly efficient and highly versatile alerting and cell killing device. Under physiological conditions, this system acts as a well-regulated cascade, protecting the organism against pathogens and participating during the initial defensive steps of humoral and cellular response. The unregulated activation of this system may cause or even aggravate diseases; therefore, its modulation is currently considered of high importance.

Areas covered: This review is a critical examination on patent literature published between 2008 and 2013. An insight is provided about the discovery and development of novel therapeutic agents. These include macromolecules, polysaccharides and proteins, specific antibodies, and hybrid or chimeric products. Peptides and low molecular weight organic compounds (natural products, their derivatives and fully synthetic molecules) are covered as well.

Expert opinion: The search of specific inhibitors of the complement cascade has become one of the Holy Grails of Medicinal Chemistry for the last 30 – 40 years, with very few cases of success. Some highly specific macromolecules are currently available as modulators of the complement. However, there is still a marked need to find new, more specific, efficient and convenient alternatives, especially suited for chronic administration, including novel inexpensive small molecule inhibitors. Analogously, despite the initial success with specific monoclonal antibodies, a vast territory is awaiting to be explored and conquered, regarding the regulation of complement activation by antibody-mediated blockage of specific polypeptides or receptor sites.     

p38 MAPK inhibitors: a patent review (2012 – 2013)

Introduction: The p38 MAPK is a ubiquitous target in the research-based pharmaceutical industry. It plays a decisive role in the regulation of the production of proinflammatory cytokines. Since novel biological therapies have revolutionized the treatment of chronic inflammatory diseases, an intensive global search is underway for small molecules for the same application.

Areas covered: Herein, the patents and the corresponding publications of international companies, which focus on the development and identification of a new generation of small-molecule p38 inhibitors, are summarized.

Expert opinion: The most promising approach is the development of linear binders, which induce a glycine flip at Gly110 of the kinase hinge region by a carbonyl oxygen atom of the respective ligand. The major focus of the patent works was the application of molecules in new indications. Previous applications were in the treatment of rheumatoid arthritis; currently, there are several new applications, including pulmonary diseases, cancer and Alzheimer's disease. Targeting p38 upstream kinases and downstream effectors has also proved to be a very promising step in the development of more effective inhibitors. A further trend is drug combination, applied to a wide range of indications, such as chronic obstructive pulmonary disease and cancer.     

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.     

Farnesyl pyrophosphate synthase modulators: a patent review (2006 – 2010)

Introduction: Farnesyl pyrophosphate synthase (FPPS, also known as farnesyl diphosphate synthase (FDPS)) is one of the key enzymes involved in the mevalonate pathway and as such is widely expressed. FPPS modulators, specifically FPPS inhibitors, are useful in treating a number of diseases, including bone-related disorders characterized by excessive bone resorption, for example, osteoporosis, cancer metathesis to bone and infectious diseases caused by certain parasites.

Areas covered: This review covers structures and applications of novel FPPS modulators described in the patent literature from 2006 to 2010. Patents disclosing new formulations and uses of existing FPPS inhibitors are also reviewed. Thirty-three patents retrieved from the USPTO, EP and WIPO databases are examined with the goal of defining current trends in drug discovery related to FPPS inhibition, and its therapeutic effects.

Expert opinion: Bisphosphonates (BPs) continue to dominate in this area, although other types of modulators are making their appearance. Remarkable for their high bone mineral affinity, BPs are structural mimics of the dimethylallyl pyrophosphate substrate of FPPS, and constitute the major type of FPPS inhibitor currently used in the clinic for treatment of bone-related diseases. Lipophilic BPs and new classes of non-BP FPPS inhibitors (salicylic acid and quinoline derivatives) have been introduced as possible alternatives for treatment of soft tissue diseases, such as some cancers. Novel formulations, fluorescent diagnostic probes and new therapeutic applications of existing FPPS inhibitors are also areas of significant patent activity, demonstrating growing recognition of the versatility and underdeveloped potential of these drugs.     

Protein kinase C inhibitors: a patent review (2010 – present)

Introduction: Protein kinase C (PKC) comprises at least 10 isoforms, pivotal in various cellular differentiation processes and in other specific cellular functions. Catalytic subunits of all PKCs are highly conserved which play a central role in the development of kinase-specific inhibitors for the treatment of a number of diseases and also in the drug resistance and immunological disorders. The authors' previous work of reviewing patents of PKC inhibitors is continued in this report.

Area covered: Thorough survey on the physiological roles of PKC isoforms and patents filed for PKC inhibitors from 2010 to present representing new and potential strategy for the cure and prevention of disorders due to elevation in various PKC levels is reported.

Expert opinion: The PKC isoforms are unique in terms of tissue distribution and an elevation in any isoform level results in different diseased conditions. Different PKC isoforms have high sequence identity but they are involved in different diseases. Crystal structure of few PKC isoforms viz. C1 domain of PKCδ, the C2 domains of PKCα and β, kinase domain and full structure of PKCβII are known. Identification of more crystal structures and thorough analysis of available structures and information on the PKC ligands will be helpful in the drug designing and development processes.