5-Lipoxygenase inhibitors: a review of recent patents (2010 – 2012)

Introduction: 5-Lipoxygenase (5-LO) is a crucial enzyme of the arachidonic acid (AA) cascade and catalyzes the formation of bioactive leukotrienes (LTs) with the help of FLAP, the 5-LO-activating protein. LTs are inflammatory mediators playing a pathophysiological role in different diseases like asthma, allergic rhinitis as well as cardiovascular diseases and certain types of cancer. With the rising number of indications for anti-LT therapy, 5-LO inhibitor drug development becomes increasingly important.

Areas covered: Here, both recent findings regarding the pathophysiological role of 5-LO and the patents claimed for 5-LO inhibitors are discussed. Focusing on direct inhibitors, several patents disclosing FLAP antagonists are also subject of this review. Novel compounds include 1,5-diarylpyrazoles, indolizines and indoles and several natural product extracts.

Expert opinion: Evaluation of the patent activities revealed only quite moderate action. Nevertheless, several auspicious drug-like molecules were disclosed. It seems that in the near future, FLAP inhibitors can be expected to enter the market for the treatment of asthma. With the resolved structure of 5-LO, structure-based drug design is now applicable. Together with the identification of downstream enzyme inhibitors and dual-targeting drugs within the AA cascade, several tools are at hand to cope with 5-LOs increasing pathophysiological roles.     

RET kinase inhibitors: a review of recent patents (2012–2015)

Introduction: Tyrosine kinases are involved in the control of several biological processes and have been recognized as hot spots of oncogenic transformation, thus representing a major therapeutic target. Dysregulated activation of RET kinase, either through point mutations or gene fusions, is accountable for a significant fraction of thyroid carcinomas, as well as a minor population of lung cancers. Two drugs are currently available for the treatment of medullary thyroid carcinoma and two additional compounds have been approved for differentiated thyroid carcinoma. Several other molecules are under preclinical and clinical evaluation.

Areas covered: This review covers the most recent patent literature (2012–2015) describing compounds with activity against the RET kinase, trying to catch a view of the next generation of potential anti-RET drugs.

Expert opinion: RET has been a focus of molecularly targeted efforts for over a decade. However, none of the drugs currently on the clinical stage were specifically developed to hit RET, which was rather an off-target. Besides, only two of four drugs have activity on metastatic medullary carcinoma. Therefore, there is still a need of additional, more potent and more specific RET inhibitors, which will hopefully emerge from the new generation of compounds disclosed in most recent patents.     

Strategies for TGF-β modulation: a review of recent patents

Background: TGF-β has been identified as a key factor in the progression of various diseases, in particular cancer and fibrosis. The signaling of TGF-β can be modulated through three distinct strategies: using antisense nucleotides that block TGF-β mRNA (trabedersen (AP 12009)), using monoclonal antibodies to block TGF-β isoforms (lerdelimumab, metelimumab) or using small molecule inhibitors of the TGF-β receptor 1 (TGF-βR1 or ALK-5). Objective: This review focuses on small molecules and summarizes the most recent TGF-βR1 inhibitors reported in the patent literature. Methods: We searched and analyzed the patent literature claiming chemical matter for TGF-βR1 inhibition from the 1^st of January 2005 to the 1^st of January 2009. Results/conclusions: The inhibition of TGF-β has recently been clinically validated with antisense nucleotide trabedersen. Small molecules inhibitors of TGF-βR1 that are now in Phase I clinical trials and in preclinical stage are, therefore, of high interest and could provide a more versatile route to TGF-β modulation through oral dosing while maintaining the same therapeutic benefits.     

Inhibitors of melanogenesis: a patent review (2009 – 2014)

Introduction: Melanogenesis is the process of producing the melanin pigment, in which a series of chemical and enzymatic pathways are involved. Modulation at any level of this process would become an important approach in the treatment of hyper- or hypopigmentation-related diseases. Since hyperpigmentation covers important issue in cosmetics, there is a need of such review to understand and update this field to the public domain.

Areas covered: In this review, authors discuss most recent melanogenesis inhibitors published in the patents since 2009. The up-to-date overview of classical catechol-based tyrosinase inhibitors to non-classical melanogenesis inhibitors with different mechanism of action is discussed. Inhibitors including small-interfering RNA and peptides from ～ 30 patents and their associated literature are also discussed.

Expert opinion: Although a huge number of melanogenesis inhibitors have been reported, the future studies should be focused towards the identification of new inhibitors with a clear mechanism. The next breakthrough in the field therefore, is likely to come from the detailed structure–activity relationship studies of thioureas with improved therapeutic profiles. Targeting other parameters such as number or size of melanosomes, maturation of melanosomes and expression of melanogenic enzymes may give the best results to overcome toxicity and other formulation problems.     

Inhaled muscarinic antagonists for respiratory diseases: a review of patents and current developments (2006 – 2010)

Introduction: Because tiotropium has demonstrated clinical benefits as a long-term maintenance treatment for chronic obstructive pulmonary disease (COPD), the number of patent applications of new chemical entities with antimuscarinic activity has significantly increased, along with the number of compounds that have reached clinical development.

Areas covered: This review summarizes the current status of long-acting muscarinic antagonists (LAMA) in clinical development for COPD, and the associated patent literature since 2006, with a focus on new chemical entities.

Expert opinion: In recent years, companies have taken different approaches to obtain compounds with high potency, long duration of action and minimal systemic exposure. Several strategies for minimizing adverse effects due to systemic exposure have been identified (quaternization, higher rate of plasma hydrolysis and degradation, increased plasma protein binding). The beneficial effects beyond bronchodilation that may be provided in the treatment of COPD patients with a LAMA, and the advantages of combination therapies, such as LAMA + LABA and LAMA + corticosteroids, have also been taken into account in recent studies.     

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.     

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.     

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.     

PDE4 inhibitors: a review of current developments (2005 – 2009)

Background: Despite the sound preclinical database and some promising data from clinical trials, development of PDE4 inhibitors for the treatment of inflammatory or neurological diseases has been hampered by dose-limiting class-related side effects. Objective: In the past years, companies opted for different approaches to improve the therapeutic window of their compounds including topical administration of PDE4 inhibitors with the goal of minimizing systemic exposure. This change in strategy is reflected by the disclosure of novel and chemically diverse molecules that demonstrate the continued interest of pharmaceutical industry in developing PDE4 inhibitors. Conclusion: This review summarizes the clinical development of PDE4 inhibitors since 2005 and the associated patent literature with a focus on strategies applied to minimize systemic adverse effects. In sum, although a significant number of new drugs designed for improved tolerability entered clinical trials, so far none of them fulfilled expectations and best progress has been achieved recently with the oral, non-isoform selective PDE4 inhibitor roflumilast.     

Review of recent acetyl-CoA carboxylase inhibitor patents: mid-2007 – 2008

Background: Acetyl-CoA carboxylase (ACC) is a biologic target that is receiving increased attention for the treatment of obesity and type 2 diabetes mellitus. Inhibition of this enzyme, either in transgenic mice or pharmacologically, has been shown to have beneficial effects on lab animals Method: This review of the ACC inhibitor patent literature covers the period from mid-2007 to December 2008, during which time a total of 18 patents were published. Conclusion: These published patent applications include ACC inhibitors that inhibit the enzyme through modulation of the carboxyltransferase-domain, inhibitors that bind to the biotin carboxylase-domain and novel chemotypes whose mode of action was not disclosed. Furthermore, published patents claim the discovery of ACC2 isoform selective and ACC1/2 non-selective inhibitors.     

1,2-Benzisoxazole compounds: a patent review (2009 – 2014)

Introduction: Benzisoxazoles represent a class of heterocyclic compounds of great importance for the preparation of biologically active compounds. Benzisoxazoles are an important structure and some benzisoxazole-based medicines have been approved for human clinical use, including atypical antipsychotics (risperidone, paliperidone and iloperidone) and an anticonvulsant (zonisamide).

Areas covered: This review puts emphasis on the recent progress in therapeutically attractive benzisoxazole derivatives especially 1,2-benzisoxazoles, which were published in the patent literature between 2009 and 2014. As for the class of medicines, the main focus is on atypical antipsychotics and potential therapeutic treatments for other CNS disorders. This review also covers the examples of benzisoxazole-based kinase inhibitors. Moreover, novel benzisoxazoles with significant therapeutic interest are also mentioned.

Expert opinion: More recent examples of structural modification of existing drugs led to the discovery of some promising benzisoxazoles for antipsychotic use. The design of multi-target ligands is important for the manipulation of pharmacological properties and safety profiles for the use of antipsychotics. Benzisoxazoles have been widely used as pharmacophores in the search for novel drug candidates in a variety of therapeutic area. It is fair to assume that the wide and frequent use of benzisoxazoles in drug discovery and development will continue into the future.     

Hedgehog pathway inhibitors: a patent review (2009 – present)

Introduction: The hedgehog (Hh) pathway is a developmental signaling pathway that plays a key role in directing cellular growth and tissue patterning during embryonic development. Dysregulation of Hh signaling has been linked to the development of a variety of human tumors, and numerous drug development programs in both academia and industry are actively exploring inhibitors of the pathway as anti-cancer agents.

Areas covered: This review surveys the recent patent literature (2009 – 2012) for Hh pathway inhibitors as treatments for a variety of human malignancies.

Expert opinion: To date, all of the pathway inhibitors that have entered clinical trials and the majority of compounds identified via high-throughput screens target smoothened (Smo), a transmembrane protein that is essential for pathway signaling. While these compounds have shown initial promise in preclinical and clinical trials, several mechanisms of resistance to Smo inhibitors have been identified. Even with this knowledge, the majority of small-molecule pathway inhibitors disclosed in the recent patent literature directly target Smo. The continued identification of Hh pathway inhibitors that function either upstream or downstream is warranted not only to combat these emerging resistance mechanisms, but also to help elucidate the various cellular mechanisms that control both normal and oncogenic pathway signaling.     

Targeting monocyte and macrophage subpopulations for immunotherapy: a patent review (2009 – 2013)

Introduction: Monocytes and macrophages are heterogeneous populations of effector cells in the innate immune system. Once thought to be obligatory precursors for macrophages, monocytes are now known to have several distinct sub-populations and their own independent functions. This separation of the two lineages has opened new therapeutic avenues in inflammation and created new technologies targeting the mononuclear phagocyte system (MPS).

Areas covered: A search of Google Patents and PatentScope has revealed numerous patents targeting monocytes and macrophages. This review will focus on seven patents from 2009 to 2013, utilizing autologous monocyte and macrophage adoptive transfer, genetic manipulation of the MPS, therapeutic nanoparticles and liposomes or combinations of these strategies. Patents that target monocyte recruitment are also briefly reviewed.

Expert opinion: While monocyte and macrophage targeting has yielded some promising results in animal models, these often fail to translate well to successful clinical trials. The paradigm of how cells in the MPS interact and evolve is constantly being updated, and caution must be exercised in developing immunomodulatory agents until this relationship is better understood.     

Therapeutic modulation of retinoid X receptors – SAR and therapeutic potential of RXR ligands and recent patents

Introduction: Retinoid X receptor (RXR) agonists have a limited role in cancer therapy with bexarotene and alitretinoin as approved drugs but their use is limited by adverse effects. Several evidence from in vitro, in vivo, and small clinical studies points to various further potential applications of RXR ligands in neurodegenerative and inflammatory diseases.

Areas covered: The authors review known RXR ligand classes with their key structure–activity relationships and recent reports on pharmacological effects of RXR modulation. Based on these aspects, the authors evaluate recent patents claiming novel RXR ligands or their use.

Expert opinion: While the use of RXR modulators has been claimed in several novel and promising indications, little progress has been made in the development of innovative rexinoids with improved (subtype-)selectivity. Next-generation RXR modulators that selectively target the RXR subtypes for individual indications may be required to exhaustively exploit the therapeutic potential of RXRs.     

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.     

Fatty acid amide hydrolase inhibitors: a patent review (2009 – 2014)

Introduction: Fatty acid amide hydrolase (FAAH) is a key enzyme responsible for the degradation of the endocannabinoid anandamide. FAAH inactivation is emerging as a strategy to treat several CNS and peripheral diseases, including inflammation and pain. The search for effective FAAH inhibitors has thus become a key focus in present drug discovery.

Areas covered: Patents and patent applications published from 2009 to 2014 in which novel chemical classes are claimed to inhibit FAAH.

Expert opinion: FAAH is a promising target for treating many disease conditions including pain, inflammation and mood disorders. In the last few years, remarkable efforts have been made to develop new FAAH inhibitors (either reversible and irreversible) characterized by excellent potency and selectivity, to complete the arsenal of tools for modulating FAAH activity. The failure of PF-04457845 in a Phase II study on osteoarthritis pain has not flattened the interest in FAAH inhibitors. New clinical trials on ‘classical’ FAAH inhibitors are now ongoing, and new strategies based on compounds with peculiar in vivo distribution (e.g., peripheral) or with multiple pharmacological activities (e.g., FAAH and COX) are under investigation and could boost the therapeutic potential of this class in the next future.     

mGluR2 positive allosteric modulators: a patent review (2009 – present)

Introduction: The mGlu2 receptor, which belongs to the group II subfamily of metabotropic glutamate receptors (mGlu) along with the mGlu3 receptor, has proven to be of particular importance in neuropharmacology. Preferentially expressed on presynaptic nerve terminals, the mGlu2 receptor negatively modulates glutamate and GABA release and is widely distributed in the brain. High levels of mGlu2 receptors are seen in brain areas such as prefrontal cortex, hippocampus and amygdala where glutamate hyperfunction may be implicated in disorders and diseases such as anxiety and schizophrenia. Given the promise offered by mGlu2/3 receptor activation, there is increased interest in identifying small molecules which activate the receptor. A preferred approach is via positive allosteric modulators (PAMs) which bind at an alternative site to agonists.

Areas covered: This review covers the patent applications which were published between April 2009 and December 2012 on PAMs of the mGlu2, and it is a continuation of an earlier review published in this journal.

Expert opinion: Advances in medicinal chemistry and pharmacology have set the stage in the field of mGlu2 receptor PAMs. Compounds currently advancing in clinical trials will soon establish the therapeutic potential of this allosteric approach.     

Emerging approaches to the treatment of uveitis: patents of 2000 – 2004

The treatment of non-infectious uveitis is often a challenging experience for both the patient and the treating physician. The use of traditional forms of treatment is restricted by limited effectiveness and considerable side effects. This review examines the current trends in therapy and the emerging new classes of therapeutic agents used in the treatment of non-infectious uveitis. It then examines some of the newer approaches apparent from recent patenting over the past four years and assesses their likely future significance.     

Aurora kinase inhibitor patents and agents in clinical testing: an update (2009 – 10)

Introduction: Mitosis is a key step in the cell cycle and is controlled by several cell cycle regulators, including aurora kinases. Aurora family members A, B and C are essential for spindle assembly, centrosome maturation, chromosomal segregation and cytokinesis. Overexpression/amplification of aurora kinases has been implicated in oncogenic transformation, including the development of chromosomal instability in cancer cells. Hence, the use of aurora kinase small molecule inhibitors as a potential molecular-targeted therapeutic intervention for cancer is being pursued by various researchers.

Area covered: This review provides an update on aurora kinase inhibitors based on developments from 2009 to 2010. The medicinal chemistry aspects of aurora kinase inhibitors, with a particular emphasis on the patent literature, are reviewed. Databases such as PubMed, SCOPUS, Scifinder and www.clinicaltrials.gov database were used to search for literature in the preparation of this review.

Expert opinion: Around a dozen aurora kinase inhibitors are currently undergoing various Phase I – II evaluations for different human cancers. Instead of being applied as a monotherapy, combinations of aurora kinase inhibitors and existing chemotherapeutic compounds seem to give better therapeutic outcomes and are, therefore, a promising future cancer therapy.