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.     

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.     

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.     

PARP inhibitors as antitumor agents: a patent update (2013-2015)

Introduction: PARP inhibitors have been extensively explored as antitumor agents and have shown potent efficacy both in vitro and in vivo. They can be used in monotherapy under the synthetic lethality concept or in combination with radiotherapy or chemotherapy, inducing a synergistic effect.

Areas covered: This review covers relevant efforts in the development of PARP inhibitors with a particular focus on recently patented PARP inhibitors, combination therapy involving PARP inhibitors, tumor responsiveness to PARP inhibitors as detailed in reports made from 2013 – 2015, and PARP drugs in clinical trials and other novel inhibitors that emerged in 2013 – 2015.

Expert opinion: Clinical studies and applications of PARP inhibitors as antitumor agents have gained considerable recognition in the last few years. In addition to FDA-approved olaparib, an increasing number of new inhibitors have been designed and synthesized, some of which are under preclinical or clinical evaluation. Novel inhibitors are still required, especially new scaffold compounds or drugs with improved properties, such as higher selectivity, higher potency and lower toxicity. The development of combination therapies involving PARP inhibitors and the exploration of biomarkers to predict outcomes with PARP inhibitors would expand the applications of these inhibitors, allowing more patients to benefit from this promising class of drugs in the future.     

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.     

Anti-norovirus therapeutics: a patent review (2010-2015)

Introduction: Human noroviruses are the primary causative agents of acute gastroenteritis and are a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. An improved understanding of norovirus biology, as well as the pathogenic mechanisms underlying the disease, has provided the impetus for a range of intense exploratory drug discovery efforts targeting viral and host factors.

Areas covered: An overview of norovirus inhibitors disclosed in the patent literature (2010-present) and Clinicaltrials.gov is presented. The review is further enriched and supplemented by recent literature reports.

Expert opinion: Seminal discoveries made in recent years, including a better understanding of the pathobiology and life cycle of norovirus, the identification and targeting of multiple viral and host factors, the advent of a replicon system and a small animal model for the preclinical evaluation of lead compounds, and the availability of high resolution X-ray crystal structures that can be utilized in structure-based drug design and lead optimization campaigns, collectively suggest that a small molecule therapeutic and prophylactic for norovirus infection is likely to emerge in the not too distant future.     

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.     

Protein tyrosine phosphatase 1B (PTP1B) inhibitors as potential anti-diabetes agents: patent review (2015-2018)

ABSTRACT

Introduction: Protein tyrosine phosphatase 1B (PTP1B) inhibition has been recommended as a crucial strategy to enhance insulin sensitivity in various cells and this fact is supported by human genetic data. PTP1B inhibitors improve the sensitivity of the insulin receptor and have the ability to cure insulin resistance-related diseases. In the latter years, targeting PTP1B inhibitors is being considered an attractive target to treat T2DM and therefore libraries of PTP1B inhibitors are being suggested as potent antidiabetic drugs.

Areas covered: This review provides an overview of published patents from January 2015 to December 2018. The review describes the effectiveness of potent PTP1B inhibitors as pharmaceutical agents to treat type 2 diabetes.

Expert opinion: Enormous developments have been made in PTP1B drug discovery which describes progress in natural products, synthetic heterocyclic scaffolds or heterocyclic hybrid compounds. Various protocols are being followed to boost the pharmacological effects of PTP1B inhibitors. Moreover these new advancements suggest that it is possible to get small-molecule PTP1B inhibitors with the required potency and selectivity. Furthermore, future endevours via an integrated strategy of using medicinal chemistry and structural biology will hopefully result in potent and selective PTP1B inhibitors as well as safer and more effective orally available drugs.     

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.     

Tryptase inhibitors: a patent review

Introduction: Tryptase is one of the main serine-proteinases located in the secretory granules of mast cells, and is released through degranulation, which is involved in the pathogenesis of allergic inflammatory disease, cardiovascular diseases, lung fibrosis and tumor. Therefore, inhibitors targeting tryptase may represent a new direction for the treatment of allergic inflammatory disease and other diseases.

Areas covered: In this article, we discussed the history and development of tryptase inhibitors and described a variety of tryptase inhibitors via their structures and biological importance in clinical studies and drug development for tryptase-related diseases.

Expert opinion: Initial tryptase inhibitors based on indole structure as the hydrophobic substituent on a benzylamine-piperidine template have low specificity and poor bioavailability. Therefore, designing new and specific inhibitors targeting tryptase should be involved in future clinical studies. Modifications toward indoles with varying N-substitution, introducing an amide bond, and growing the chain length contribute to an increase in the specific selectivity and potency of tryptase inhibitors. Tryptase has become the research hotspot to explore many related diseases. Therefore, there has been growing appreciation for the potential importance of the tryptase inhibitors as a target for treating these diseases.     

An updated patent review on P-glycoprotein inhibitors (2011-2018)

Introduction: P-glycoprotein is a complex ATP-ase transporter involved in physiological and pathological functions. In particular, it is involved in the onset of multidrug resistance in cancer, in ocular disease, Chronic Rhinosinusitis, CNS diseases such as Alzheimer, Parkinson, and epilepsy. One of the aims of clinicians and pharmacologists is to monitor P-gp activity through the inhibitors and to use its activity and/or expression in physiological barriers for the early diagnosis of several pathologies. Considering P-glycoprotein activity, several substrates have been characterized but the challenge is to design ‘pure’ P-glycoprotein inhibitors.

Area covered: P-glycoprotein inhibitors display a large spectrum of activities. Here the contents of patents focused on the role of P-glycoprotein inhibitor in modulating MDR in cancer, in bioavailability, in ocular disease and Chronic Rhinosinusitis are reported.

Expert opinion: the use of P-glycoprotein inhibitor sic et simpliciter, or in coadministration with therapeutic agents, for ocular disease, and Chronic Rhinosinusitis is promising and could be suggested for additional trials. By contrast, the bioavailability of the coadministrated drugs, increased by P-glycoprotein inhibitor, deserves a wider discussion, in particular on the pharmacokinetic aspect of both P-glycoprotein inhibitor and the coadministered drug.     

MEK inhibitors in oncology: a patent review (2015-Present)

Introduction: The RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways have been identified as promising therapeutic targets for cancer therapy. Over-activation of these pathways and their components including gene mutations has been considered as one of the major causes of melanoma. Mitogen-activated protein kinase (MEK) is a downstream kinase of RAS pathway found in two different forms MEK1/2. The MEK inhibitors in combination with other kinase/mutant gene inhibitors have shown promising results in patients with metastatic melanoma.

Areas covered: A comprehensive review of the patent literature (2015 – Present) on MEK inhibitors, their combinations with other kinase inhibitors and structural insights has been highlighted.

Expert opinion: Recently mitogen-activated protein kinase (MEK) inhibitors have attracted considerable interest in oncology especially in melanoma. The MEK inhibitors showed promising results in patients with metastatic melanoma harboring mutant genes such as BRAF, KRAS. The MEK1/2 inhibitors in combination with BRAF, KRAS and/or PI3K inhibitors showed promising results in mutated colorectal, pancreatic adenocarcinoma, solid tumor, and relapsed/refractory melanoma. The combination delays the onset of acquired resistance, resulting in increased progression-free and overall survival. The combination and/or multi-targeted kinase/mutant gene inhibitors may be a therapeutic option for the personalized cancer treatment of patients with relapsed or refractory multiple myeloma.     

An updated patent review: xanthine oxidase inhibitors for the treatment of hyperuricemia and gout (2011-2015)

Introduction: Xanthine oxidase (XO) is a versatile molybdoflavoprotein, widely distributed, occurring in milk, kidney, lung, heart, and vascular endothelium. Catalysis by XO to produce uric acid and reactive oxygen species leads to many diseases. Anti hyperuricemic therapy by xanthine oxidase inhibitors has been mainly employed for the treatment of gout.

Area covered: This review covers the patent literature (2011–2015) and also presents the interesting strategies/rational approaches employed for the design of xanthine oxidase inhibitors reported recently.

Expert opinion: Recent literature indicates that various non purine scaffolds have been extensively investigated for xanthine oxidase inhibition. The significant potential endowed by heteroaryl based compounds, in particularly fused heterocycles clearly highlights their clinical promise and the need for detailed investigation. Studies by various research groups have also revealed that the flavone framework is open for isosteric replacements and structural modifications for yielding potent non purine xanthine oxidase inhibitors. In addition, various plant extracts recently reported to possess significant xanthine oxidase inhibitory potential presents enough promise to initiate a screening program for the identification of other plant extracts and phytoconstituents possessing inhibitory potential towards the enzyme.     

Gelatinase inhibitors: a patent review (2011-2017)

Introduction: Gelatinase represents a promising biotarget in new drug development as it is closely related to various pathological events, including but not limited to neoplasm, aging, respiratory and neurological disorders. Gelatinase inhibitors are thereby designated as chemotherapeutics or as mechanistic probe to figure out the unrecognized functions of MMP members.

Areas covered: The focus of this article is to highlight recently issued patents concerning the naturally available or synthetic gelatinase inhibitors (2011–2017), where the chemical structures, SAR investigation, biological application. Besides, the binding modes of representative inhibitors with gelatinase are also briefly described.

Expert opinion: The access of crystallographic structure of inhibitor complexed with gelatinase, the availability of pharmacophoric features of gelatinase inhibitors, together with the proper use of drug design protocols, have paved the way for developing more selective and potent modulators. Moreover, considering typical bio-assessment was primarily concentrated on the antitumor effect, the other bioactivity outcomes should also be concerned to look for new application of gelatinase inhibitors.     

Cholinesterase inhibitors: a patent review (2007 - 2011)

INTRODUCTION: Cholinesterase inhibitors participate in the maintenance of the levels of the neurotransmitter acetylcholine by inhibiting the enzymes implicated in its degradation, namely, butyrylcholinesterase and acetylcholinesterase. This pharmacological action has an important role in several diseases, including neurodegenerative diseases such as Alzheimer's. AREAS COVERED: This article reviews recent advances in the development of cholinesterase enzyme inhibitors, covering the development of new chemical entities, new pharmaceutical formulations with known inhibitors or treatments in combination with other drug families. EXPERT OPINION: The development of cholinesterase inhibitors has to face several issues, including the fact that the principal indication for these drugs, Alzheimer's disease, is not currently believed to derivate from a cholinergic deficiency, although most of the drugs clinically used for these disease are cholinesterase inhibitors. Moreover, the adverse effects found when administering cholinesterase inhibitors limit their use in other diseases, such as gastrointestinal diseases, glaucoma, or analgesia.     

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.     

Autotaxin inhibitors: a patent review (2012-2016)

Introduction: Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA) and choline. The ATX/LPA axis has received increasing interest in recent years because both the enzyme ATX and the bioactive lipid LPA are involved in various pathological conditions such as tumor progression and metastasis, fibrotic diseases, autoimmune diseases, arthritis, chronic hepatitis, obesity and impaired glucose homeostasis. Thus, a great effort has been devotd in developing synthetic ATX inhibitors as new agents to treat various diseases including cancer and fibrotic diseases.

Areas covered: This review article summarizes the autotaxin inhibitors presented in patent literature from October 2012 to August 2016 and their biological evaluation, discussing their activities in vitro and in vivo.

Expert opinion: During the recent years, there has been an intensive effort on the discovery of potent and selective ATX inhibitors. Although various synthetic inhibitors have been developed, only limited studies for their in vivo activity have been reported so far. A decade after the first claim of synthetic ATX inhibitors in 2006, one inhibitor has been in clinical trials for idiopapthic pulmonary fibrosis. The use of ATX inhibitors seems an attractive strategy to produce novel medicinal agents, for example anticancer agents.     

Dipeptidyl peptidase IV inhibitors as a potential target for diabetes: patent review (2015-2018)

Introduction: Dipeptidyl peptidase 4 (DPP-4) belongs to the family of serine proteases and is involved in the degradation of GLP-1 and GIP hormones, which enhance the production and release of insulin. Targeting DPP-4 inhibitors is increasingly being considered as promising paradigms to treat type 2 diabetes mellitus and therefore DPP-4 inhibitors are being considered as promising antidiabetic drugs.

Areas covered: This review provides an overview of published patents describing natural and synthetic DPP-4 inhibitors from January 2015 to December 2018.

Expert opinion: A fair number of new synthetic and natural DPP-4 inhibitors have been reported in the last four years which describe the progress in the development of various heterocyclic scaffolds or heterocyclic hybrid compounds. As a result of this, many marketed DPP-4 inhibitors that have been approved by the appropriate governing bodies during the past decade, have been introduced as inhibitors. Molecular hybridization is an emerging idea in medicinal chemistry and therefore hybrid compounds of DPP-4 inhibitors with other DPP-4 inhibitors or with antidiabetic drugs should be formulated for a comprehensive evaluation. More detailed pharmacovigilance of DPP-4 inhibitors is required because this will address the pancreas-related adverse events as well as their impact on cardiovascular outcomes via long-term studies.     

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.