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.     

An overview of investigational antiapoptotic drugs with potential application for the treatment of neurodegenerative disorders

Importance of the field: The increase in life expectancy in developed countries has given rise to several emerging social problems. Of particular note is the dramatic rise in the incidence of neurodegenerative diseases. Given this new social scenario, there is a need to identify therapeutic strategies to delay the advance of these pathologies, for which no effective treatment is currently available.

Areas covered in this review: The present review discusses some of the drugs that are now under development with antiapoptotic activity or currently on the market that may have a potential application for the treatment of neurodegenerative diseases. Moreover, we also comment on potential compounds such as resveratrol and melatonin. Despite the lack of information from clinical trials on these two compounds, they are attracting considerable attention because of their natural origin and antioxidant and antiapoptotic action. Furthermore, they do not show toxicity in humans. In addition, we discuss the potential application of several compounds, such as NMDA antagonists, JNK inhibitors and GSK-3 inhibitors, for the treatment of neurodegenerative disorders.

What the reader will gain: This article will review recent developments in the field of apoptosis inhibitors, which might provide future tools for the treatment of the neurodegenerative diseases.

Take home message: The treatment of neurodegenerative diseases is a major challenge in medicine. This is partly because the incidence of these disorders is expected to rise in the coming years. New developments in the field of apoptosis inhibitors may provide future tools for the treatment of the aforementioned neurodegenerative diseases.     

HtrA proteins as targets in therapy of cancer and other diseases

Importance of the field: The HtrA family proteins are serine proteases that are involved in important physiological processes, including maintenance of mitochondrial homeostasis, apoptosis and cell signaling. They are involved in the development and progression of several pathological processes such as cancer, neurodegenerative disorders and arthritic diseases.

Areas covered in this review: We present characteristics of the human HtrA1, HtrA2 and HtrA3 proteins, with the stress on their function in apoptosis and in the diseases. We describe regulation of the HtrAs' proteolytic activity, focusing on allosteric interactions of ligands/substrates with the PDZ domains, and make suggestions on how the HtrA proteolytic activity could be modified. Literature cited covers years 1996 – 2010.

What the reader will gain: An overview of the HtrAs' function/regulation and involvement in diseases (cancer, neurodegenerative disorders, arthritis), and ideas how modulation of their proteolytic activity could be used in therapies.

Take home message: HtrA2 is the best target for cancer drug development. An increase in the HtrAs' proteolytic activity could be beneficial in cancer treatment, by stimulation of apoptosis, anoikis or necrosis of cancer cells, or by modulation of the TGF-β signaling cascade; modulation of HtrA activity could be helpful in therapy of neurodegenerative diseases and arthritis.     

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.     

Inhibitors of the kynurenine pathway as neurotherapeutics: a patent review (2012–2015)

Introduction: The proven pathological alterations in the kynurenine pathway of tryptophan metabolism, either in preclinical models of neurological and psychiatric disorders or in human samples themselves, elicited numerous attempts to restore the altered balance via pharmaceutical manipulation of the pathway.

Areas covered: The aim of the authors was to conduct a review of relevant scientific data on enzyme inhibitors of the kynurenine pathway, with special attention to pipeline drug development strategies based on relevant patent literature, covering the period of 2012–2015. Considering the magnitude of the topic, only the most prominent examples of lead compounds and substances necessary to enlighten structure activity relationships were reported.

Expert opinion: Although the clinical and preclinical data are reassuring, there is a lack of applicable drugs in daily clinical practice. However, the recent determination of enzyme structures considerably promoted the development of potent inhibitors, most of them having been designed as a structural analog of the natural enzyme substrate. Especially, the inhibition of indolamine 2,3-dioxygenase in central nervous system tumors, the inhibition of kynurenine aminotransferase in cognitive dysfunction, and the inhibition of kynurenine 3-monooxygenase in neurodegenerative disorders, such as Huntington’s disease, each show great promise.     

Soluble epoxide hydrolase inhibitors: a patent review

Importance of the field: Soluble epoxide hydrolase (sEH) inhibitors have been shown to effectively increase the levels of epoxyeicosatrienoic acids and reduce the levels of dihydroxyeicosatrienoic acids, which may be translated to therapeutic potentials for multiple disease indications. It has been claimed that sEH inhibitors can be used to treat hypertension, diabetes, stroke, dyslipidemia, pain, immunological disorders, eye diseases, neurological diseases and other indications.

Areas covered in this review: A comprehensive synopsis of patent literature on sEH inhibitors is provided.

What the reader will gain: A total of more than 100 patent publications describing multiple classes of sEH inhibitors are analyzed. These include amides, ureas, thioamides, thioureas, carbamates, acyl hydrazones, chalcone oxdies, etc. In addition to selected in vitro and in vivo data of representative sEH inhibitors, a wide range of proposed applications of sEH inhibitors are also summarized.

Take home message: Several sEH inhibitors with potent in vitro and in vivo target inhibition appear promising, including one Phase II clinical candidate. The clinical evaluation will be critical to assess the proclaimed therapeutic utility of sEH inhibition.     

c-Jun N-terminal kinase inhibitors: a patent review (2010 – 2014)

Introduction: c-Jun N-terminal kinases (JNKs) are involved in the emergence and progression of diverse pathologies such as neurodegenerative, cardiovascular and metabolic disorders as well as inflammation and cancer. In recent years, several highly selective pan-JNK inhibitors have been characterized and three chemical entities targeting JNKs have been investigated in clinical trials.

Areas covered: This review summarizes patents claiming inhibitors of all JNK isoforms published between 2010 and 2014. Although primarily focusing on the patent literature, relevant peer-reviewed publications related to the covered patents have also been included. Moreover, key patents claiming novel applications of previously published chemical entities are reviewed. The article highlights a total of 28 patents from nine pharmaceutical companies and academic research groups.

Expert opinion: Although some selective pan-JNK inhibitors with reasonable in vivo profiles are now available, little is known about the isoform selectivity required for each particular indication and the development of isoform-selective JNK inhibitors still represents a challenge in JNK drug discovery. Moreover, isoform-selective tool compounds are a prerequisite to a comprehensive understanding of the biology of each JNK isoform. Potential approaches towards such compounds include the design of type-II and type-I¹/₂ binders, which are absent in the current JNK inhibitor portfolios, as well as the design of novel allosteric inhibitors. Furthermore, covalent inhibition, which already led to the first high-quality probe for JNKs, might be further exploited for gaining selectivity and in vivo efficacy. With regard to a potential therapeutic application, the recently proposed concept of covalent reversible inhibitors is expected to be attractive.     

SHIP2 and its involvement in various diseases

Importance of the field: Inositol polyphosphate 5-phosphatase (SHIP2) is an important negative regulator of intracellular phosphatidylinositol phosphate, a key second messenger of various intracellular signaling pathways. The functional upregulation of SHIP2 results in signaling blockade, leading to related disorders.

Areas covered in this review: We first summarize the role of SHIP2 in the regulation of insulin signaling and type 2 diabetes, including remarkable advances in pharmacological approaches. In addition, this review highlights new findings regarding the involvement of SHIP2 in a number of diseases, including cancer, neurodegenerative diseases, and atherosclerosis.

What the reader will gain: Recently identified small-molecule inhibitors of SHIP2 phosphatase activity emphasize the potential therapeutic value of SHIP2. In addition, currently available evidence demonstrates the importance of the scaffolding-type protein function of SHIP2. Understanding this interesting function will help clarify the complicated involvement of SHIP2 in various disorders.

Take home message: Recent studies have demonstrated that SHIP2 is a promising therapeutic target for not only type 2 diabetes, but also cancer, neurodegenerative diseases, and atherosclerosis. Targeting SHIP2 through specific small-molecule inhibitors will have beneficial effects on these diseases.     

Bicyclic bis-heteroaryl derivatives as inhibitors of the α-synuclein protein: a patent evaluation of WO2018138088A1

ABSTRACT

Introduction: Neurodegenerative diseases commonly present misfolding and aggregation of one or more proteins, including α-synuclein, β-amyloid, and tau. Several research efforts have been made to develop therapeutic agents able to reduce the neurotoxic effects of aggregated proteins. Among these, inhibition of α-synuclein by small molecules has been considered as a promising approach.

Areas covered: Bis-heteroaryl derivatives based on the N‐[1‐(1H‐indol‐3‐yl)hexan‐2‐yl]‐1,3‐thiazole‐5‐carboxamide scaffold with different heterocyclic substitutions at the 2-thiazole position showed interesting ability to inhibit self-aggregation of α-synuclein in vitro and were claimed as potential therapeutics for various neurodegenerative diseases. The potential of the presented compounds is evaluated with respect to other similar small molecule modulators of protein aggregation reported in the patent literature.

Expert opinion: The compounds presented with ability to inhibit aggregation of α-synuclein in vitro in the low micromolar range. The biggest drawback of the presented application is the absence of pharmacokinetic, toxicity, and in vivo efficacy data. On the other hand, the number of applications in this area by UCB Biopharma SPRL (four published in last 2 years) and promising pharmacokinetic and in vivo data disclosed in a previous patent on similar molecules, indicate that these compounds may hold value as therapeutic agents for neurodegenerative disorders.     

Therapeutic uses of furin and its inhibitors: a patent review

Introduction: Since the discovery of furin, numerous reports have studied its role in health and diseases, including cancer, inflammatory and infectious diseases. This interest has led to the development of both large protein- and peptide-based inhibitors aiming to control furin activity to treat these disorders. The most recent advances include the development of potent peptidomimetic furin inhibitors, considerably expanding the field of therapeutic applications.

Area covered: In this review, the use of furin or its inhibitors for therapeutic conditions is described through the patent literature since 1994. Only compounds with biological efficacy or augmented properties demonstrated within the patent literature or the associated publications concerning their claimed uses are discussed.

Expert opinion: Considering the diseases that may benefit from furin inhibition, several patents detail the use of the restricted number of furin inhibitors. However, there have been recent reports of new scaffolds, and even the use of furin itself, as a therapeutic agent. Despite considerable evidence of in vivo efficacy, limited confirmation from clinical trials supports or refutes the further use of these compounds in a therapeutic context. The most advanced application is the use of furin knockdown in the generation of an autologous cancer vaccine, which has initiated clinical trials.     

Urinary trypsin inhibitor as a therapeutic option for endotoxin-related inflammatory disorders

Importance of the field: Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used as a drug for patients with inflammatory disorders such as pancreatitis, shock and disseminated intravascular coagulation (DIC). Previous in vitro studies have demonstrated that serine protease inhibitors may have anti-inflammatory properties at sites of inflammation. However, the therapeutic effects of UTI in vivo remain unclarified, as commercial UTI has been developed to act against humans, with the activity and selectivity toward the relevant animal UTI being less characterized.

Areas covered in this review: In this review, we introduce the roles of UTI in experimental endotoxin (lipopolysaccharide; LPS)-related inflammatory disorders using UTI-deficient (-/-) and corresponding wild-type mice.

What the reader will gain: Our experiments using genetic approach suggest that endogenous UTI can protect against the systemic inflammatory response and subsequent organ injury induced by LPS, at least partly, through the inhibition of pro-inflammatory cytokine and chemokine expression, which provide important in vivo evidence and understanding about a protective role of UTI in inflammatory conditions.

Take home message: Using genetically targeted mice selectively lacking UTI, UTI has been evidenced to provide an attractive ‘rescue’ therapeutic option for endotoxin-related inflammatory disorders such as DIC, acute lung injury and acute liver injury.     

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.     

Casein kinases as potential therapeutic targets

Introduction: The conventional term ‘casein kinase’ (CK) denotes three classes of kinases – CK1, CK2 and Golgi-CK (G-CK)/Fam20C (family with sequence similarity 20, member C) – sharing the ability to phoshorylate casein in vitro, but otherwise unrelated to each other. All CKs have been reported to be implicated in human diseases, and reviews individually dealing with the druggability of CK1 and CK2 are available. Our aim is to provide a comparative analysis of the three classes of CKs as therapeutic targets.

Areas covered: CK2 is the CK for which implication in neoplasia is best documented, with the survival of cancer cells often relying on its overexpression. An ample variety of cell-permeable CK2 inhibitors have been developed, with a couple of these now in clinical trials. Isoform-specific CK1 inhibitors that are expected to play a beneficial role in oncology and neurodegeneration have been also developed. In contrast, the pathogenic potential of G-CK/Fam20C is caused by its loss of function. Activators of Fam20C, notably sphingolipids and their analogs, may prove beneficial in this respect.

Expert opinion: Optimization of CK2 and CK1 inhibitors will prove useful to develop new therapeutic strategies for treating cancer and neurodegenerative disorders, while the design of potent activators of G-CK/Fam20C will provide a new tool in the fields of bio-mineralization and hypophosphatemic diseases.     

Inhibitors of cathepsin C (dipeptidyl peptidase I)

Importance to the field: Cathepsin C (dipeptidyl peptidase I) plays a key role in the activation of several degradative enzymes linked to tissue destruction in inflammatory diseases. Thus, cathepsin C inhibitors could potentially be effective therapeutics for the treatment of such diseases as chronic obstructive pulmonary disease and cystic fibrosis.

Areas covered in this review: Although this article focuses on cathepsin C inhibitor patents, the journal literature concerning small molecule inhibitors of the enzyme is also covered comprehensively (1981 – 2009).

What the reader will gain: It is our aim to give the reader a complete overview of the cathepsin C inhibitor chemotypes that have been disclosed to date. In addition, key biological data have been included for both irreversible and reversible inhibitors.

Take home message: All known cathepsin C inhibitors are believed to have a covalent interaction with the Cys-234 residue of the enzyme. The electrophilic and sometimes peptidic nature of these molecules is associated with poor metabolic stability and is also a potential safety concern. Thus, overcoming developability issues is a serious hurdle for these compounds and there can be little doubt that this is the principal reason why no cathepsin C inhibitors appear to have reached clinical development so far.     

Itk inhibitors: a patent review

Importance of field: IL-2 inducible T-cell kinase (Itk) is a non-receptor tyrosine kinase of the Tec family. It plays an important role in T cell signaling and the production of various pro-inflammatory cytokines such as IL-2, IL-4, IL-5, IL-10 and IL-13. Inhibition of Itk has been a target for the treatment of diseases related to inflammation disorders such as psoriasis and allergic asthma. Rich resources on the structural information for Itk made discovery of novel selective Itk inhibitors blossom in the past decade.

Areas covered in this review: In this report, distinct structural classes of specific Itk inhibitors are summarized and their in vitro/in vivo properties are discussed.

What the reader will gain: A summary of 21 patents including 16 different chemical structure classes of Itk inhibitors. The in vivo efficacies of some of the inhibitors in animal models are also discussed.

Take home message: Although some of the inhibitors show efficacy in different animal models, which implies potential for therapeutic use in human, there is not yet a chemical entity reported in clinical trials. The prospects for Itk inhibitors will rely on the quality of the compound and the validity of the target in patients within the selected therapeutic area.     

Patent Evaluation: Novel 3-Indolyl Thioacetate Derivatives as NMDA Receptor Antagonists

Summary

Novelty: New 3-indolylthioacetate derivatives are disclosed as NMDA antagonists. The compounds are claimed to be useful in treating convulsions, ischaemia, hypoxic or hypoglycaemic conditions and neurodegenerative diseases. They also have an anxiolytic effect.

Biology: Anticonvulsant properties are assessed in vivo by inhibition of quinolinic acid-induced seizures in mice, where the control group has a statistically higher seizure rate than mice administered intracerebroventricularly with the test compound. Anti-epileptic activity is assessed by inhibition of audiogenic convulsion (one hundred and ten decibels for thirty seconds) in mice with similiar results. The anxiolytic effect is measured by blocking the ultrasonic vocalization in rat pups in vivo when removed from the litter, again the two groups show statistical differences.

Chemistry: Synthesis, by conventional methods, of the starting material, the 3,5-dichlorophenylhydrazone of ethyl pyruvate, and of eleven compounds is presented. Characterization is by Mp, IR and NMR. The preferred compound is 2-carboxyethyl-4,6-dichloroindole. A large number of compounds are claimed.     

Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014-2015)

Introduction: Glycogen synthase kinase (GSK-3) is a serine/threonine kinase that phosphorylates more than one hundred different sequences within proteins in a variety of different pathways. It is a key component of a remarkably large number of cellular processes and diseases. Imbalance of GSK-3 activity is involved in various prevalent pathological diseases, such as diabetes, neurodegenerative diseases and cancer. Understanding its role in different disorders has been central in the last several decades and there has been a significantly large development of GSK-3 inhibitors, some of which, show promising results for the treatment of these devastating diseases.

Areas covered: This review covers patent literature on GSK-3 inhibitors and their applications published and/or granted between 2014 and 2015.

Expert opinion: GSK-3 inhibitors have gained a prominent role in regenerative medicine based in their ability to modulate stem cells. Moreover, some allosteric modulators of GSK-3 emerge as safe compounds for chronic treatments.     

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.     

Targeting mitochondrial dysfunction in neurodegenerative disease: Part I

Importance of the field: The socioeconomic burden of an aging population has accelerated the urgency of novel therapeutic strategies for neurodegenerative disease. One possible approach is to target mitochondrial dysfunction, which has been implicated in the pathogenesis of numerous neurodegenerative disorders.

Areas covered in this review: This review examines the role of mitochondrial defects in aging and neurodegenerative disease, ranging from common diseases such as Alzheimer's and Parkinson's disease to rare familial disorders such as the spinocerebellar ataxias. The review is provided in two parts; in this first part, we discuss the mitochondrial defects that have been most extensively researched: oxidative stress; bioenergetic dysfunction and calcium deregulation.

What the reader will gain: This review provides a comprehensive examination of mitochondrial defects observed in numerous neurodegenerative disorders, discussing therapies that have reached clinical trials and considering potential novel therapeutic strategies to target mitochondrial dysfunction.

Take home message: This is an important area of clinical research, with several novel therapeutics already in clinical trials and many more in preclinical stages. In part II of this review we will focus on possible novel approaches, looking at mitochondrial defects which have more recently been linked to neurodegeneration.     

Emerging drugs for lysosomal storage diseases

Importance of the field: Because orphan drug regulations encouraged development of drugs for rare disorders by granting marketing exclusivity for many years and other commercial benefits, treatment has become achievable for a few lysosomal storage disorders also. The presently available therapies, however, are not able to address all aspects of these multisystemic disorders and do not cure the patient. Therefore, there is a need for producing new drugs that are based on known pathophysiological mechanisms, such as enzyme replacement or inhibition of substrate synthesis, or which use new approaches to prevent the build-up of storage material.

Areas covered in this review: New compounds that are being designed by different pharmaceutical companies can be divided in two groups, enzyme targeted and substrate targeted drugs. Enzyme targeted drugs include substances that modify the enzyme to make it more accessible to organs such as the bone or the brain, enhance enzyme activity (chaperones) or activate enzyme synthesis by small molecules that induce read-through of premature stop codons of genes that bear a nonsense mutation. To the group of substrate targeted drugs belong substances that inhibit the synthesis or modify the structure of the substrate (substrate deprivation or substrate optimization, respectively). For this review, a literature research has been undertaken that covers the years 1968 – 2010.

What the reader will gain: The reader of this paper will get an overview of drugs for lysosomal storage disorders that are on the market or are under development. This will help in the understanding of the pathophysiological mechanisms that underlie these rare metabolic diseases. In addition, the reader should realize that the increasing number of these very expensive drugs may lead to significant consequences for the health economic system.

Take home message: In the last years, the interest of scientists and pharmaceutical companies in lysosomal storage disorders has increased dramatically, leading to the production of a rising number of different drugs. These drugs act at several stages of the pathophysiological cascade, for example, at the level of the substrate (substrate deprivation) or of the enzyme (enzyme enhancement). The presently available treatments are not able to address all clinical manifestations of these disorders, and it will still take a long time until new drugs are developed that are capable of curing the patients.