Serine protease inhibitors to treat inflammation: a patent review (2011-2016)

Introduction: Inflammation is a physiological part of the complex biological response of tissues to counteract various harmful signals. This process involves diverse actors such as immune cells, blood vessels, and nerves as sources of mediators for inflammation control. Among them serine proteases are key elements in both physiological and pathological inflammation.

Areas covered: Serine protease inhibitors to treat inflammatory diseases are being actively investigated by various industrial and academic institutions. The present review covers patent literature on serine protease inhibitors for the therapy of inflammatory diseases patented between 2011 and 2016.

Expert opinion: Serine proteases regulating inflammation are versatile enzymes, usually involved in proinflammatory cytokine production and activation of immune cells. Their dysregulation during inflammation can have devastating consequences, promoting various diseases including skin and lung inflammation, neuroinflammation, and inflammatory arthritis. Several serine proteases were selected for their contribution to inflammatory diseases and significant efforts that are spread to develop inhibitors. Strategies developed for inhibitor identification consist on either peptide-based inhibitor derived from endogenous protein inhibitors or small-organic molecules. It is also worth noting that among the recent patents on serine protease inhibitors related to inflammation a significant number are related to retinal vascular dysfunction and skin diseases.     

EZH2 inhibitors: a patent review (2014-2016)

Introduction: The histone methyltransferase EZH2 is the catalytic subunit of the PRC2 complex involved in H3K27 trimethylation. Aberrant PRC2 activity has been reported in several cancers and EZH2 overexpression has been associated with poor outcome in different tumors. EZH2 somatic mutations and deletions was found in lymphomas, myelodysplastic and myeloproliferative disorders and associated with higher H3K27me3 levels. Numerous chemical entities have been studied as EZH2 inhibitors in the recent years and some of them entered the cancer clinical arena.

Areas covered: This review summarizes recent efforts in the drug development of EZH2 inhibitors reported in the patent literature covering the 2014–2016 period, and their potential use as therapeutics mainly in cancerous diseases.

Expert opinion: Despite the number of compounds described, only a few of them entered the clinical arena. Moreover, most of the compounds developed share a common 2-pyridone ring pharmacophore. Recently, secondary mutants have been described to be resistant to the standard EZH2 inhibitors treatment. Based on these data a lot of effort is still required to find new chemical entities that inhibit EZH2 directly, or indirectly (via PRC2 disruption). Several issues are still to be settled, such as drug resistance and the importance of selectivity over EZH1 or somatic EZH2 mutants.     

LpxC inhibitors: a patent review (2010-2016)

Introduction: The Zn²⁺-dependent deacetylase LpxC is an essential enzyme of lipid A biosynthesis in Gram-negative bacteria and a promising target for the development of antibiotics selectively combating Gram-negative pathogens. Researchers from industry and academia have synthesized structurally diverse LpxC inhibitors, exhibiting different LpxC inhibitory and antibacterial activities.

Areas covered: A brief introduction into the structure and function of LpxC, showing its suitability as antibacterial target, along with the structures of several reported LpxC inhibitors, is given. The article reviews patents (reported between 2010 and 2016) and related research publications on novel small-molecule LpxC inhibitors. Emphasis is placed on structure-activity relationships within the reported series of LpxC inhibitors.

Expert opinion: The performed analysis of patents revealed that the current search for novel LpxC inhibitors is focused on small molecules, sharing common structural features like a Zn²⁺-chelating group as well as a highly lipophilic side-chain. However, despite the promising preclinical data of many of the reported compounds, besides the recently withdrawn clinical candidate ACHN-975, no other LpxC inhibitor has entered clinical trials. The lack of clinical candidates might be related with undesired effects caused by the common structural elements of the LpxC inhibitors.     

VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012-2016)

Introduction: Angiogenesis is an important component of certain normal physiological processes, but aberrant angiogenesis contributes to some pathological disorders and in particular to tumor growth. Activation of vascular endothelial growth factor receptor-2 (VEGFR-2) by vascular endothelial growth factor (VEGF) is a critical step in the signal transduction pathway that initiates tumor angiogenesis. Inhibition of angiogenesis via blocking VEGF/VEGFR-2 signaling pathway has emerged as a potential approach to anticancer therapy. Indeed, this approach has recently been clinically validated with the approvals of VEGFR-2 inhibitors.

Areas covered: This review accounts for small-molecule inhibitors and antibodies of VEGFR-2 reported in the patent literature covering between January 2012 and June 2016, and their potential use as therapeutics for cancers, angiogenesis-related disorders and inflammatory diseases.

Expert opinion: Despite the attractiveness of anti-angiogenic therapy by VEGF inhibition alone, several issues may limit this approach. VEGF expression levels can be elevated by numerous diverse stimuli such as the activation of other RTK signaling transduction pathway. Therefore, the development of multi-targeted tyrosine kinase inhibitors and the strategy of using these agents in conjunction with other anti-cancer agents are recent interesting therapeutic approaches that could give promising results.     

Ectonucleotidase inhibitors: a patent review (2011-2016)

Introduction: Ectonucleotidases are a broad family of metallo-ectoenzymes that are responsible for hydrolysing a variety of nucleotides to nucleosides, hence orchestrating the activation of P1 and P2 cell receptors via controlled release of nucleotides and nucleosides. Many disorders such as impaired calcification including aortic calcification, neurological and immunological disorders, platelet aggregation, cell proliferation and metastasis. are characterized by an increase in expression of these ectonucleotidases. Consequently, selective inhibitors of ectonucleotidases are required for therapeutic intervention.

Area covered: Several classes of compounds such as purine, nucleotide derivatives (e.g., ARL67156) and monoclonal antibodies, have shown promising ectonucleotidase inhibitory potential. This review discusses chemistry and therapeutic applications of ectonucleotidase inhibitors patented from 2011 to 2016.

Expert opinion: All eukaryotic cells express nucleotide and nucleoside receptors on their cell surface and are capable of releasing extracellular nucleotides. Ectonucleotidases are a broad family of metallo-ectoenzymes that hydrolyze a variety of nucleotides to nucleosides. These extracellular nucleotides and nucleosides are important cell signalling molecules and mediate a variety of (patho)physiological processes by acting upon their respective P1 and/or P2 receptors. Discovery of molecules that can selectively inhibit or activate ectonucleotidases is crucial from therapeutic point of view, since it allows human intervention into purinergic cell signalling, thereby allowing us to modulate related (patho)physiological processes as desired.     

Urate transporter URAT1 inhibitors: a patent review (2012 - 2015)

Introduction: Human urate transporter 1 (URAT1, encoded by SLC22A12) has been identified as a key urate transporter expressed at the apical membrane of renal proximal tubule cells for regulating urate homeostasis. Therefore, URAT1 is an attractive target for the development of new uricosurics against hyperuricemia. Discovery of novel inhibitors targeting URAT1 has become a research hotspot in recent years.

Areas covered: In this paper, we reviewed the patent applications and related research published during the years 2012–2015, covering the development of URAT1 inhibitors.

Expert opinion: There are some promising and inspiring patent applications in this area. Several compounds have superior inhibitory activity of URAT1 with the availability of urate-lowering treatment. For new drug development and commercialization, further studies are needed to evaluate the efficacy and safety.     

Leucine-rich repeat kinase 2 inhibitors: a patent review (2014-2016)

Introduction: Leucine-rich repeat kinase 2 (LRRK2) is a member of the Tyrosine Kinase-Like (TKL) branch of the kinome tree and is a multi-domain protein that includes GTPase and kinase activity. While genome-wide association studies (GWAS) has linked LRRK2 with Crohn’s disease and leprosy, it has received the greatest attention due to it being implicated as one of the genetic loci associated with autosomal dominant inheritance in Parkinson’s disease (PD).

Areas covered: In this review, the small molecule patent literature from 2014–2016 with a focus on composition of matter and use patents was surveyed. Scifinder was primarily searched using ‘LRRK2? as the query to identify all relevant literature and then triaged for small molecule patents.

Expert opinion: The patent landscape around LRRK2 continues to develop. The early patents covered using existing kinase inhibitors for use against LRRK2. This evolved to compounds specifically designed for selectivity against LRRK2, but key exemplified compounds lacked sufficient brain exposure to affect sufficient efficacy. More recent compounds have addressed this deficiency and show greater potential for treating PD. While potency will be necessary to generate medicines with low human daily doses, brain penetration and safety will be the key differentiators for ultimately determining the most effective LRRK2 disease-modifying treatment for PD.     

Autotaxin inhibitors: a perspective on initial medicinal chemistry efforts

The lysophospholipase D enzyme, autotaxin (ATX), has been linked to numerous human diseases including cancer, neurophatic pain, obesity and Alzheimer's disease. Although the ATX protein was initially purified and characterized in 1992, a link to bioactive lipid metabolism was not made until 2002. In the past decade, metal chelators, lysophospholipid product analogs, and more recently, small non-lipid inhibitors of the enzyme were successfully identified. The majority of these inhibitors have been characterized using recombinant purified ATX in vitro, with very few examples studied in more complex systems. Translation of ATX inhibitors from the hands of medicinal chemists to clinical use will require substantially expanded characterization of ATX inhibitors in vivo.     

DNA methyltransferase inhibitors: an updated patent review (2012-2015)

Introduction: DNA methyltransferases (DNMTs), important enzymes involved in epigenetic regulation of gene expression, represent promising targets in cancer therapy. DNMT inhibitors (DNMTi), which can modulate the aberrant DNA methylation pattern in a reversible way via inhibiting DNMT activity, have attracted significant attention in recent years.

Areas covered: This review outlines the newly patented inhibitors targeting DNMTs, mainly incorporating small molecular inhibitors and oligonucleotide derivatives. The chemical structures, biological activity, and the encouraging clinical research in progress are delineated in detail.

Expert opinion: Two drugs, azacitidine and decitabine, have evidently shown efficacy in hematologic malignancies, yet do not work well on solid tumors, have low specificity, substantial toxicity, and poor bioavailability. With the rapid advancement in systems biology, drug combinations, such as DNMTi, in conjugation with histone deacetylase inhibitors (HDACi) or immunotherapy, probably serve as an efficient way of implementing epigenetic therapy. Meanwhile, the resolved autoinhibitory structures of DNMTs afford a novel strategy for targeting the protein-protein interface involved in the autoinhi-bitory interactions. The molecular mechanism underlying the conformational transitions would also shed new light on the design of allosteric inhibitors. Both strategies would produce inhibitors with more selectivity compared to nucleotide derivatives.     

Ursolic acid derivatives for pharmaceutical use: a patent review (2012-2016)

Introduction: Ursolic acid (UA), belongs to a group of pentacyclic triterpenoids and is known to possess some very interesting biological properties. Protocols have been developed in order to synthesize bioactive UA analogs which have resulted in numerous ursolic acid analogs being synthesized during the period 2012–2016. Ursolic acid and its analogues can be employed to treat various cancers, inflammatory diseases, diabetes, Parkinson’s disease, Alzheimer’s disease, hepatitis B, hepatitis C and AIDS to mention but a few.

Areas covered: This review covers patents on therapeutic activities of ursolic acid (UA) and its synthetic derivatives published during the four year period 2012–2016. A discussion about structure-activity relationships (SAR) of these analogs is also included.

Expert opinion: Ursolic acid and its synthetic derivatives demonstrated excellent anticancer, antidiabetic, antiarrhythmic, anti-hyperlipidemic, antimicrobial, anti-hypercholesterolemic, and anti-cardiovascular properties. Additionally, various ursolic acid analogues have been synthesized through modification at positions C₂-OH, C₃-OH and C_17-CO₂H. It is noteworthy that the C-17 amide and amino analogs of UA possessed better anticancer activity compared to the parent compound (UA). Most importantly, UA has the potential to conjugate with other anticancer drugs or be transformed into its halo derivatives since this will greatly facilitate scientists to get lead compounds in cancer drug discovery.     

Tyrosinase inhibitors: a patent review (2011-2015)

Introduction: Tyrosinase is responsible for melanin production. The overproduction of melanin causes many skin disorders. The inhibition of tyrosinase activity would appear to be the most rational and explicit way of overcoming these issues.

Areas covered: Thirty eight patents on synthetic tyrosinase inhibitors issued since 2011 were reviewed. Inhibitors were categorized by chemical structure and assigned to eight classes. Information on potent inhibitors in each class is provided.

Expert opinion: Many tyrosinase inhibitors of natural or synthetic origin have been identified, but very few are qualified for clinical use. Thus medicinal scientists have to work more on the identification of potent and safe tyrosinase inhibitors. Various chemical scaffolds have been explored. Among them, the scaffolds such as resorcinol, biaryl, imidazolethione, β-phenyl-α,β-unsaturated carbonyl, and some double strand oligonucleotides have shown high tyrosinase inhibition, low toxicities, and great potencies. Detail structure activity relationship studies of these potential scaffolds could provide directions for a new and potent tyrosinase inhbitors. Furthermore new trends, such as the use of synergistic phenomena, salt formation, drug repositioning and designing of multi-targeted tyrosinase inhibitors could expand search areas for much improved tyrosinase inhibitors.     

Cathepsin B and L inhibitors: a patent review (2010 - present)

Introduction: Cathepsins play an important role in protein degradation and processing. Aberrant cathepsin B or L is closely associated with many serious diseases such as cancer, osteoporosis and autoimmune disorders. Therefore, development of potent and selective cathepsin B and L inhibitors has aroused much attention in recent years. Although several classes of cathepsin inhibitors are presently available, there are still some problems to solve, such as broad-spectrum inhibition to protease, specially cysteine proteases, which lead to unpredictable side effects in clinical trials. Therefore, it is very necessary to discovery new scaffolds and new application of cathepsin B and L inhibitors for developing therapeutic agents for treating diseases mediated by cathepsin B or L.

Areas covered: This updated review summarizes new patents on cathepsin B and L inhibitors from 2010 to present.

Expert opinion: The review gives the latest development in the area of inhibitors of cathepsin B and L, which have been considered key therapeutic targets for the development of drugs treating related diseases. This review puts emphasis on the discovery of novel small molecule inhibitors of cathepsin B and L, as well as their new application as new therapeutic agents.     

A patent review of Monoacylglycerol Lipase (MAGL) inhibitors (2013-2017)

Introduction: Monoacylglycerol lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid 2-arachidonoylglycerol. Because of this key role, selective inactivation of MAGL represents an interesting approach to obtain desirable effects in several diseases. Furthermore, MAGL is upregulated in cancer cells and primary tumors and its inhibition in aggressive breast, ovarian, and melanoma cancer cells impairs cell migration, invasiveness, and tumorigenicity.

Areas covered: This review covers patent literature on MAGL inhibitors and their applications published from 2013 to 2017.

Expert opinion: MAGL inhibition has gained considerable importance in many therapeutic fields and one compound has been subjected to Phase I studies. Even if a reasonable number of patents have been recently reported, novel MAGL inhibitors are still required, especially novel chemical classes displaying a reversible mechanism of action.     

Mcl-1 inhibitors: a patent review

Introduction: The myeloid cell leukemia?1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Over-expression of MCL-1 has been closely related to tumor progression as well as to resistance, not only to traditional chemotherapies but also to targeted therapeutics including BCL-2 inhibitors such as ABT-263. Therefore, there has been extensive research and development in the last decade in both academic and industrial settings to address this unmet medical need.

Areas covered: This review covers the research and patent literature of the past 10 years in the field of discovery and development of small-molecule inhibitors of the MCL-1 anti-apoptotic protein.

Expert opinion: Small-molecule strategies to disrupt the protein-protein interactions between MCL-1 and its pro-apoptotic counterparts, such as BAK and BIM, have recently emerged. Several small-molecules based on different scaffolds describe promising in vitro data as MCL-1 selective inhibitors. While many lead compounds remain at the in vitro preclinical development stage, the two most recent patent applications describe promising in vivo data, and one small molecule inhibitor has recently entered into clinical development. It is such an exciting moment that the long awaited clinical studies will generate some insight into the therapeutic potential of this anti-cancer approach, and possibly facilitate the further development of other early stage inhibitors.     

LSD1 inhibitors: a patent review (2010-2015)

Introduction: Lysine demethylase 1 (LSD1) plays an important role in mediating the expression of genes involved in cancer and non-cancer diseases such as viral infections, cardiovascular and neurodegenerative disorders. It is involved in a number of processes from adipogenesis to cell adhesion to viral latency, regulating several cell pathways related with proliferation, development, and cell cycle control. Numerous chemical entities have been studied in recent years and some of them entered the clinical arena.

Areas covered: This review summarizes recent efforts in the drug development of LSD1 inhibitors reported in the patent literature covering the 2010-2015 period, including their potential use as therapeutics in cancerous, neurological, inflammatory, cardiovascular, and viral diseases.

Expert opinion: The development of novel potent and selective LSD1 inhibitors is ongoing, in order to improve their potency and selectivity against specific types of cancer or non-cancer diseases. More in-depth studies are required to assess the role of LSD1 inhibitors in the expression of LSD1 target genes, for a better assessment of the biochemistry underlying their efficacy, and to provide evidence for any possible side effects. Furthermore, an interesting therapeutic approach is the use of LSD1 inhibitors in conjunction with other epidrugs to combine their therapeutic potential, leading to innovative, personalized treatments.     

Immune checkpoint inhibitors: a patent review (2010-2015)

Introduction: Immune checkpoint inhibitors, like anti-PD-1/PD-L1 antibodies, are revolutionizing therapeutic concepts in the treatment of cancer. Said class of drugs will represent a multi-billion dollar market over the coming decade. Many companies have therefore developed important patent activities in the field.

Areas covered: The present review gives an overview of the patent literature during the period 2010-2015 in the field of immune checkpoint inhibitors. In particular, the review presents a selection of international patent applications related to inhibitors of PD-1/PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs and CD39.

Expert opinion: Immune checkpoint inhibitors are now widely accepted as a key component of the therapeutic strategies in cancer. This fervent activity creates a maze of third-party patents that pose considerable risks for both newcomers and established companies. We can thus anticipate that the number of patent conflicts and disputes will increase in the near future. Treatments will involve combination therapy comprising at least one immune checkpoint inhibitor and companies will multiply patent filings in this field. Finally, we can expect that patents related to biomarkers that will render a patient eligible to a treatment with an immune checkpoint inhibitor will have tremendous commercial value.     

Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2011-2015)

Introduction: Hypoxia-inducible factor (HIF)-1α regulates the expression of genes involved in angiogenesis, cellular energy metabolism, and cell survival during cancer development. The increased expression of HIF-1α in most solid tumors is associated with poor prognoses and therapeutic outcomes. Therefore, HIF has been recognized as an attractive target for cancer therapy, and many HIF inhibitors have been reported.

Areas covered: This patent survey summarizes the information about patented HIF inhibitors over the last 5 years (2011–2015).

Expert opinion: Although many of the HIF inhibitors reviewed in this patent survey possess inhibitory activity against cancer and HIF-related diseases, the compounds are still in the early stages of development, most likely due to the complexity of the HIF-1 pathway and their different mechanisms of action for HIF inhibition. Most cancer cells use the glycolytic pathway for energy production and HIF-1α participates deeply in the expression of several glycolytic enzymes. Therefore, a detailed study of HIF’s function in cancer metabolisms may provide us an alternative strategy for further development of HIF inhibitors in cancer therapy.     

Coumarin derivatives: an updated patent review (2015-2016)

Introduction: Coumarins belong to the benzopyrone family. They are naturally plant-derived or synthetically obtained substances, presenting a wide variety of biological activities, offering an extented therapeutic profile. Their structural characteristics correlated to physicochemical properties define their pleiotropic biological responses.

Areas covered in this review: Recent patent publications (2015–2016), describing coumarins and their derivatives are analyzed. Synthesis, biological evaluations in vitro /in vivo e.g. antiviral, anticancer, cytotoxic, antioxidant, anti-inflammmatory protocols are included. Furthermore, several pharmaceutical applications and pharmaceutical compositions are also described.

Expert opinion: Several synthetic coumarins, hybrids and derivatives (azoles, sulfonyl, furazan, pyrazole etc) have been found to possess promising anticancer, antitumor anti-proliferative activities. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action is well defined can serve as lead compounds for the design of new more potent molecules.