Leucine-rich repeat kinase 2 inhibitors: a patent review (2006 – 2011)

Introduction: Leucine-rich repeat kinase 2 (LRRK2) has received considerable attention since the discovery of LRRK2 mutations in families with dominantly inherited Parkinson's disease (PD) in 2004. The missense mutation G2019S is the most common LRRK2 mutation and has been identified in both familial and sporadic PD cases. The G2019S mutation enhances kinase activity suggesting that LRRK2 could be an attractive therapeutic target for PD and small-molecule ATP-competitive LRRK2 kinase inhibitors are one way to investigate this possibility.

Areas covered: Currently, LRRK2 kinase inhibitors are being actively pursued by industry and academia. Herein, patents detailing the discovery of LRRK2 kinase inhibitors from 2006 through 2011 and the corresponding publications from 2006 through July of 2012 are summarized.

Expert opinion: Wild-type and mutant forms of LRRK2 are currently being actively pursued as therapeutic targets for the potential treatment of PD. The increasing number of patent applications being filed for inhibitors of LRRK2 is a testament to this activity. Numerous distinct chemo-types have been reported as LRRK2 inhibitors with some demonstrating exceptional potency and selectivity for LRRK2 relative to other kinases. These compounds are being used as pharmacological ‘tools' to elucidate the physiological and pathophysiological function of LRRK2 and it appears likely that some will be investigated for their potential therapeutic effects for the treatment of PD.     

Sphingosine kinase inhibitors: a review of patent literature (2006-2015)

Introduction: Sphingosine kinase (SphK1 & SphK2) is the sole source of the pleiotropic lipid mediator, sphingosine-1-phosphate (S1P). S1P has been implicated in a variety of diseases such as cancer, Alzheimer’s disease, sickle cell disease and fibrosis and thus the biosynthetic route to S1P is a logical target for drug discovery.

Areas covered: In this review, the authors consider the SphK inhibitor patent literature from 2006–2016 Q1 with the emphasis on composition of matter utility patents. The Espacenet database was queried with the search term ‘sphingosine AND kinase’ to identify relevant literature.

Expert opinion: Early inhibitor discovery focused on SphK1 with a bias towards oncology indications. Structurally, the reported inhibitors occupy the sphingosine ‘J-shaped’ binding pocket. The lack of cytotoxicity with improved SphK1 inhibitors raises doubt about the enzyme as an oncology target. SphK2 inhibitors are featured in more recent patent applications. Interestingly, both SphK1 and SphK2 inhibition and gene ‘knockout’ share opposing effects on circulating S1P levels: SphK1 inhibition/gene ablation decreases, while SphK2 inhibition/gene ablation increases, blood S1P. As understanding of S1P’s physiological roles increases and more drug-like SphK inhibitors emerge, inhibiting one or both SphK isotypes could provide unique strategies for treating disease.     

Targeting leucine-rich repeat kinase 2 in Parkinson's disease

Introduction: Parkinson's disease (PD), is a common progressive neurodegenerative disorder, and missense mutations in the LRRK2 gene are the most common single genetic cause of autosomal dominant PD and polymorphic variants modulate risk in sporadic PD. Earlier research focused on LRRK2 genetics, but with the recent discoveries of LRRK2 substrates/interactors, LRRK2-specific mechanisms are being unveiled.

Areas covered: As a multi-domain protein, LRRK2 possess diverse functions that range from housekeeping, signaling to clearance of proteins. Proteins that interact with LRRK2 have drawn attention to several pathophysiologic pathways that could potentially be targeted in the development of new therapies. This review will discuss the possible physiological roles of LRRK2 based on recently reported interactors as well as place LRRK2 in the disease context. Current LRRK2 inhibition studies and reports about LRRK2 biomarkers will also be discussed as they are important considerations for LRRK2 translational treatment options.

Expert opinion: The discovery of LRRK2 as a pathogenic gene in PD has contributed enormously to our understanding of clinical genetics. One of the challenges is to understand the physiologic role of LRRK2 and its specific function that gets disrupted when it is mutated. In vivo LRRK2 models have provided insights but they do not full recapitulate human PD. The identification of LRRK2 interactors opens the opportunities for identification of new therapeutic targets. Ways of quantification of kinase activity in vivo and determining what constitutes physiologic inhibition will need to be further investigated before specific pharmacologic agents can be meaningfully utilized.     

Sulfonamides: a patent review (2008 – 2012)

Introduction: The primary sulfonamide moiety is present in many clinically used drugs, such as diuretics (furosemide, indapamide, chlorthalidone, thiazides); carbonic anhydrase (CA) inhibitors (CAIs) (including acetazolamide, dichlorophenamide, dorzolamide and brinzolamide); antiepileptics (zonisamide and sulthiame); the antipsychotic sulpiride and the cycloxygenase 2 (COX2) inhibitors celecoxib and valdecoxib. Recently, novel drugs have been launched, such as apricoxib and pazopanib, which also incorporate this group.

Areas covered: The article presents the main classes of sulfonamides investigated between 2008 and 2012. Specifically, the authors review the scientific and patent literature on CAIs, COX2 inhibitors, pazopanib and its congeners, which are multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit.

Expert opinion: Most patents deal with sulfonamide CAIs incorporating NO-donating moieties as antiglaucoma agents, or with compounds targeting the tumor-associated isoforms CA IX/XII. The antidandruff actions of sulphonamides, which inhibit yeast CAs, were also claimed. Apricoxib (a COX2 inhibitor) and pazopanib, a tyrosine kinase inhibitor, show significant antitumor activity and several patents deal with these drugs. There is a constant need of novel sulfonamides to act as selective antiglaucoma drugs (targeting CA II), as antitumor agents/diagnostic tools (targeting CA IX/XII), and to treat and diagnose other disease. This privileged structural motif is likely to be present in other drugs in the future.     

Can the increasing number of newly developed leucine-rich repeat kinase 2 inhibitors validate or invalidate a potential disease-modifying therapeutic approach for Parkinson's disease?

Leucine-rich repeat kinase 2 (LRRK2) is considered an attractive therapeutic target for potential disease-modifying treatment of Parkinson's disease (PD). Both genetic and cell biological evidence have contributed to the hypothesis that LRRK2 kinase inhibition may have therapeutic potential in PD. This hypothesis was widely translated in drug discovery programs as illustrated by the growing number of patents covering newly discovered LRRK2 kinase inhibitors and emanating from at least 20 different public and private research organizations. With work still under way, this research shows the feasibility of developing potent, selective and brain permeable LRRK2 kinase inhibitors. The growing availability of these pharmacological tools should contribute to filling in the gaps in our knowledge on the safety and efficacy of LRRK2 kinase inhibition and validate/invalidate this therapeutic strategy for further development. Validation criteria should include a lack of toxic effects following long-term treatment with inhibitors as well as confirmation of target engagement in cells and animal models leading to improvement of pathological features in phenotypic assays. The state of advancement of the field of LRRK2 is such that existing biological tools and expertise can be combined with the increasing number of available LRRK2 kinase inhibitors to address these key issues.     

Inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4): a patent review (2012-2015)

Introduction: IRAK4 is located proximal to TLR/IL-1 receptors, and in preclinical studies, inhibits downstream signaling from these receptors. The development of novel small molecule inhibitors of this kinase has the potential to lead to new therapeutics to treat diseases such as rheumatoid arthritis, lupus, and lymphomas.

Areas covered: The aim of this review is to summarize the recent patent literature (2012–2015) surrounding small molecule inhibitors of IRAK4. Specific examples of the chemical matter from each patent will be discussed, including any data that are presented for the examples highlighted.

Expert opinion: There are currently many examples of highly potent and kinase selective IRAK4 inhibitors and some have been tested in various in vivo disease models, demonstrating robust pre-clinical efficacy. Several compounds appear to have the ‘drug-like’ properties to advance to the clinic, with Pfizer having already initiated several phase I studies.     

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.     

Protein kinase CK2 inhibitors: a patent review

Introduction: CK2 is a pleiotropic, ubiquitous and constitutively active protein kinase, localized in both cytosolic and nuclear compartments, where it catalyzes the phosphorylation of hundreds of proteins. CK2 is generally described as a tetramer composed of two catalytic (α and/or α′) and two regulatory subunits (β), however, the free α/α′ subunits are catalytically active by themselves. CK2 plays a key role in several physiological and pathological processes and has been connected to many neoplastic, inflammatory, autoimmune and infectious disorders. In the last 20 years, several inhibitors of CK2 have been discovered though only one of these, CX-4945, has recently entered into Phase II clinical trials as potential anticancer drug.

Areas covered: The main objective of the present review is to describe the development of CK2 activity modulators over the years according to the timeline of their patent registration.

Expert opinion: CK2 was discovered in 1954, but the first patent on CK2 modulators was deposited only 50 years later, in 2004. However, in the last 5 years an increasing number of patents on CK2 inhibitors have been registered, reflecting an increased interest in this kind of drug candidates and their possible therapeutic applications.     

Novel therapies for glaucoma: a patent review 2007 – 2011

Introduction: Glaucoma affects a large number of people, and therapies for its management are based on the use of adrenergic agonist/antagonists, carbonic anhydrase (CA) inhibitors and prostaglandin (PG) analogs. However, no new drugs have been launched on the market, although some new drug classes, such as 5-hydroxy-tryptamine (5HT₂) agonists and rho kinase inhibitors entered into advanced clinical investigations.

Areas covered: The main classes of clinically used antiglaucoma drugs, as well as potential new targets (e.g., 5HT₂ agonist, rho kinase inhibitor, RNA interference), are reviewed. A patent literature review covering the period 2007 – 2011 is presented.

Expert opinion: Most of the patents deal with sulfonamide CA inhibitors incorporating nitric oxide donating moieties or with PG analogs based on the latanoprost scaffold. The PG analogs are the predominant patented compounds. Several new potential targets emerged (e.g., rho kinase inhibitors), but no such derivatives progressed to the clinic due to adverse effects. There is an urgent need of new antiglaucoma drugs/approaches to treat and diagnose this disease in the very near future.     

Targeting LRRK2 in Parkinson’s disease: an update on recent developments

Introduction: LRRK2 research has progressed significantly in recent years with more reports of LRRK2 interactors and the development of more specific and sophisticated LRRK2 kinase inhibitors. Identification of bone fide LRRK2 substrates will provide new therapeutic targets in LRRK2-linked Parkinson’s disease (PD).

Areas covered: This review aims to put current LRRK2 research into perspective. Beginning with recent LRRK2 mammalian models employed for in vivo validation of LRRK2 substrates, followed by updates on reported LRRK2 interactors and their inferred mechanisms. Finally an overview of commonly used LRRK2 kinase inhibitors will be depicted.

Expert opinion: Identification of LRRK2 non-kinase functions suggests the possibility of alternative LRRK2 drug target sites and these should be further explored. Studies on the effects of LRRK2 kinase inhibition on its non-kinase function and its self-regulatory role will provide further insights on its pathophysiologic mechanisms. Development of robust measurements of LRRK2 inhibitor efficacy will be required. These would include identification of specific imaging ligands or direct biochemical assays that can accurately capture its intrinsic activity. Testing of new therapeutic drug targets in both LRRK2 carriers and non LRRK2-linked patients will be important since their phenotype is similar.     

Update on lymphocyte specific kinase inhibitors: a patent survey

Importance of the field: Lck (p56^lck or lymphocyte specific kinase) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T cell receptor (TCR)-mediated signaling, leading to normal T-cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection.

Areas covered in this review: This review covers the patents, patent applications and associated publications for small molecule kinase inhibitors of Lck since 2005 and attempts to place them in context from a structural point of view.

What the reader will gain: Readers will gain an overview of the structural classes and binding modes of Lck inhibitors, the major players in this area and an insight into the current state of the field.

Take home message: The search for a potent and orally active inhibitor of Lck has been an intense area of research for a number of years. Despite tremendous efforts, the identification of a highly selective and potent Lck inhibitor suitable for use as an immunosuppressive agent remains elusive.     

2-Indolinone a versatile scaffold for treatment of cancer: a patent review (2008–2014)

Introduction: 2-Indolinone is a well-known aromatic heterocyclic organic compound. A lot of work has been done on this bicyclic structure by academic and company researchers to synthesize compounds directed to a plethora of molecular targets in order to discover new drug leads. This review presents up-to-date information in the field of cancer therapy research based on this small building block.

Areas covered: The present review gives an account of the recent patent literature (2008–2014) describing the discovery of 2-indolinone derivatives with selected therapeutic activities. In this period, a large amount of patents were published on this topic. We have limited the analysis to 37 patents on 2-indolinone derivatives having potential clinical application as chemotherapeutic agents. In this review, the therapeutic applications of 2-indolinone derivatives for the treatment of cancer reported in international patents have been discussed.

Expert opinion: 2-Indolinone is the scaffold of the compounds considered from a medicinal chemistry perspective. Many of them have been developed and marketed for therapeutic use. In cancer chemotherapy, progress has been made in designing selective 2-indolinone derivatives. Some of them show preclinical efficacy. However, 2-indolinone has not exhausted all of its potential in the development of new compounds for clinical applications and remains a great tool for future research.     

A survey of small molecule glucagon receptor antagonists from recent patents (2006 – 2010)

Introduction: The ever increasing prevalence of type 2 diabetes mellitus (T2DM) in the developed and developing nations calls for the introduction of new and more effective treatments. Glucagon receptor (GCGR) antagonists are highly validated in preclinical models of T2DM and thus have the potential to be developed as a new therapy. Small molecule GCGR antagonists have been an active area of research since the 1990s. As evidenced from the number of patents and laboratories involved, these efforts have accelerated during the last decade.

Areas covered: During the period 2006 – 2010, there were numerous patent publications from several laboratories claiming the discovery of novel small molecule GCGR antagonists. Herein, we present our interpretation of these new patent publications as well as follow-up disclosures appearing in the peer-reviewed literature. This paper provides an up-to-date overview of the field of small molecule GCGR antagonism as a potential treatment for T2DM. Attempts were made wherever possible to identify preferred or representative compounds from the patent applications reviewed. In vitro and in vivo data are also discussed where they were disclosed.

Expert opinion: The novel small molecule GCGR antagonists reviewed here represent many diverse structural motifs. Some molecules are very potent antagonists of the GCGR in in vitro assays with acceptable selectivity. Some have intriguing in vivo activity in models of T2DM in a variety of preclinical species. It is to be hoped that clinical developments following these preclinical discoveries might result in a long-awaited new treatment for T2DM.     

Sulfonamide inhibitors: a patent review 2013-present

Introduction: Sulfonamide compounds are significant class of synthetic bacteriostatic antibiotics still which used today for the therapy of bacterial infections and those caused by other microorganisms. They are also known as sulfa drugs and were the main source of therapy against bacterial infections before the introduction of penicillin in 1941. Additionally, The first sulfonamide section is present inmany clinically used drugs such as diuretics, carbonic anhydrase inhibitors and antiepileptics.

Areas covered in this review: The article presents the main classes of sulfonamide inhibitors investigated between 2013 and present. Specifically, the authors review the scientific and patent literature on tyrosine kinase, human immunodeficieny virus protease-1 (HIV?1), histone deacetylase 6, protein tyrosine phosphatase 1B, sphingosine kinase, phosphatidyl inositol 3-kinase, angiogenesis, pyrazole kinase, tyrosyl DNA phosphodiesterase inhibitors were evaluated.

Expert opinion: Sulfonamides are utilized as the antiviral HIV protease inhibitor amprenavir, as an anticancer agent, and in Alzheimer’s disease drugs. All these data show that although known for more than 100 years, the primary sulfonamides constitute an important class of compounds which leads to highly valuable drugs and drug candidates for many conditions, such as cancer, glaucoma, inflammation, dandruff, just to mention the most investigated ones.     

Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 2

Introduction: Janus kinases (JAKs) are a family of four enzymes; JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) that are critical in cytokine signalling and are strongly linked to both cancer and inflammatory diseases. There are currently two launched JAK inhibitors for the treatment of human conditions: tofacitinib for Rheumatoid arthritis (RA) and ruxolitinib for myeloproliferative neoplasms including intermediate or high risk myelofibrosis and polycythemia vera.

Areas covered: This review covers patents claiming activity against one or more JAK family members in the period 2013–2015 inclusive, and covers 95 patents from 42 applicants, split over two parts. The authors have ordered recent patents according to the primary applicant’s name, with part 2 covering J through Z.

Expert opinion: Inhibition of JAK-family kinases is an area of growing interest, catalysed by the maturity of data on marketed inhibitors ruxolitinib and tofacitinib in late stage clinical trials. Many applicants are pursuing traditional fast-follower strategies around these inhibitors, with a range of chemical strategies adopted. The challenge will be to show sufficient differentiation to the originator compounds, since dose limiting toxicities with such agents appear to be on target and mechanism-related and also considering that such agents may be available as generic compounds by the time follower agents reach market.     

Small molecule HIV entry inhibitors: Part II. Attachment and fusion inhibitors: 2004 – 2010

Introduction: The first US FDA approved HIV entry inhibitor drug Enfuvirdine belongs to the fusion inhibitor category. Earlier efforts in this area were focused on peptides and monoclonal antibodies; recently, the focus has shifted towards the development of small molecule HIV attachment and fusion inhibitors. They can be used for prophylactic purposes and also hold potential for the development of HIV microbicides.

Areas covered: In a previous paper (‘Small molecule HIV entry inhibitors: Part I’), we reviewed patents and patent applications for small molecule chemokine receptor antagonists from major pharmaceutical companies. In this paper, the development of small molecule HIV attachment and fusion inhibitors is discussed in detail. It covers patents and patent applications for small molecule HIV attachment and fusion inhibitors published between 2004 and 2010 and related literature with a focus on recent developments based on lead generation and lead modification.

Expert opinion: To augment the potency of currently available antiretroviral drug combinations and to fight drug-resistant virus variants, more effective drugs which target additional steps in the viral replication cycle are urgently needed. HIV attachment and fusion processes are such targets. Inhibitors of these targets will provide additional options for the treatment of HIV drug-resistant strains. Small molecule HIV attachment inhibitors such as BMS-378806 and analogs from Bristol Myers Squibb, N-aryl piperidine derivatives from Propharmacon, and NBD-556 and NBD-557 from New York Blood Center may have potential as vaginal microbicidal agents and can be an economical alternative to monoclonal antibodies.     

5-hydroxytryptamine subtype 6 receptor modulators: a patent survey

Importance of the field: Among the GPCR subclasses that have been discovered to date, 5-HT receptors are especially attractive as key biological targets with enormous clinical importance. In particular, during the last decade, the 5-HT₆ receptor has gained increasing attention due to extensive cellular functions. It has also been suggested that its activity can be mediated by inverse agonists.

Areas covered in this review: Summarizing the points listed above, the current review primarily focuses on patent literature within the title field, evolution and trends that have not yet been covered in such depth in other published papers.

What the reader will gain: To obtain a clear understanding of the situation and dynamics within the field of 5-HT₆ ligands, having an obvious pharmaceutical potential in terms of related patents, we provide a comprehensive search through several key patent collections. We have covered promising small molecule compounds which are being evaluated in different clinical trials as well as drugs currently available in the pharmaceutical market. In addition, readers will gain a deep insight into the patent specification, geographic distribution, tendency and patent holders presented.

Take home message: Several of 5-HT₆-targeted compounds are reasonably regarded as powerful drug candidates for the treatment of a range of neuropathological disorders, including Alzheimer's disease and Huntington's disease.     

Small molecule inhibitor of apoptosis proteins antagonists: a patent review

Introduction: The family of inhibitor of apoptosis proteins (IAPs) plays a key role in the suppression of proapoptotic signaling; hence, a small molecule that disrupts the binding of IAPs with their functional partner should restore apoptotic response to proapoptotic stimuli in cells. The continued publication of new patent applications of IAP antagonists over the past 4 years is a testament to the continued interest surrounding the IAP family of proteins.

Areas covered: This review summarizes the IAP antagonist patent literature from 2010 to 2014. Monovalent and bivalent Smac mimetics will be covered as well as two new developments in the field: IAP antagonists coupled to or merged with other targeted agents and new BIR2 selective IAP antagonists.

Expert opinion: In addition to the well-explored scaffolds for monovalent and bivalent Smac-mimetics, some companies have taken more drastic approaches to explore new chemical space – for example, fragment-based approaches and macrocyclic inhibitors. Furthermore, other companies have designed compounds with alternative biological profiles – tethering to known kinase binding structures, trying to target to the mitochondria or introducing selective binding to the BIR2 domain. An overview of the status for the four small molecule IAP antagonists being evaluated in active human clinical trials is also provided.