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.     

Selectin inhibitors: a patent review

Importance of the field: Selectins play a significant and well-documented role in inflammation and immune response. They initiate tethering and rolling of blood borne leukocytes leading to their activation, adhesion and subsequent extravazation into tissues. This is important for healthy immune response and tissue repair. However, dysregulation of selectins leads to exacerbation of disease. Atherosclerosis, restenosis, deep venous thrombosis and tumor metastasis are just a few of the diseases in which selectin blockade has been demonstrated to ameliorate disease pathology. Thus, selectins remain attractive targets for amelioration of disease.

Areas covered in this review: Summarized here are new patents/patent applications on selectin inhibition published since our last review in 2003 and any significant changes or progress made in demonstrating clinical safety and efficacy of therapeutics covered by patents/patent applications reviewed in 2003.

What the reader will gain: A comprehensive review of new developments in the field of selectin inhibition through discussion of patents/patent applications from 2003 to August 2009, reports on clinical results where available and selected literature.

Take home message: The field of selectin inhibition has matured significantly in recent years in the ability to inhibit selectin/ligand interactions with drug-like molecules and to demonstrate disease modification in human trials.     

环氧酮肽类蛋白酶体抑制剂的研究进展

随着硼替佐米和卡非佐米被FDA批准用于多发性骨髓瘤患者的治疗,蛋白酶体已成为一种越来越热门的抗肿瘤药物的靶点。环氧酮肽类化合物由于其良好的选择性和较低的不良反应已成为蛋白酶体抑制剂的研究热点。本文主要综述蛋白酶体的结构和功能、环氧酮肽类蛋白酶体抑制剂的作用机制及发展现状。     

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.     

A patent review of IDO1 inhibitors for cancer

Introduction: Indoleamine 2,3-dioxygenase 1 (IDO1) is overexpressed by cancer cells and the antigen presenting dendritic cells in the tumor microenvironment (TME). Activation of IDO1 depletes tryptophan and produces kynurenine, which induces T cell anergy and suppresses tumor control by the immune system. When combined with an immune checkpoint inhibitor, IDO1 inhibitors have shown promising anticancer activity in preclinical tumor models as well as in early stage clinical trials.

Areas covered: IDO1 inhibitors disclosed in the patent literature from 2013-2017 are categorized, when applicable, according to their structural similarity to the clinical development candidates indoximod and PF-06840003, navoximod, epacadostat, KHK2455 and aryl-1,2-diamines, and BMS-986205 among others, respectively. Representative structures and their IDO1 inhibitory activity are presented to highlight the novelty and activity. Finally, the reported cocrystal structures were analyzed to provide insights for inhibitor-enzyme interactions and guidance for the design and discovery of next generation inhibitors.

Expert opinion: This review demonstrates that the structural diversity of new IDO1 inhibitors could be expanded via a number of approaches.     

Thiadiazole inhibitors: a patent review

Introduction: Four isomeric structures of thiadiazole motifs have outstanding pharmacological inhibitory applications are reported in this review. Thiadiazole nucleus is present in several biologically active natural products and commercial drugs. Most of thiadiazoles reported herein are emphasized to have broad spectrum of medicinal activities.

Areas covered: This review represents the recent inhibitory activities of thiadiazole isomeric scaffolds and their broad-spectrum biological applications published as full texts during 2010–2016 as well as the patents published during 2005–2016. The inhibition areas covered included anti-inflammatory, antimicrobial, antitumor, antioxidant, antitubercular, antiviral, antileishmanial, anticonvulsant, herbicidal and algicidal activities in addition to enzymes, human platelet aggregation and neuroprotective inhibitors.

Expert opinion: This survey revealed very interesting data about the applications of thiadiazoles, where some synthetic or natural thiadiazole derivatives were components of drugs available in the market. Many thiadiazole derivatives can be considered as lead compounds for drug synthesis. The most inhibitory active 1,3,4-thiadiazole compounds are those incorporating secondary alkyl(aryl)amido- and/or benzylthio(mercapto) groups at positions 2 and 5. Several thiadiazole derivatives demonstrated higher antibacterial, antitumor and antiviral activities than the standard drugs. Some thiadiazole derivatives exhibited high selective enzymes inhibitory activities based on the electronic properties of the substituents at positions 2 or 5.     

Factor XIa inhibitors: A review of the patent literature

Introduction: Anticoagulants are the mainstay for prevention and/or treatment of thrombotic disorders. Each clinically used anticoagulant is associated with significant adverse consequences, especially bleeding. Factor XIa (FXIa), a key factor involved in the amplification of procoagulation signal, has been suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding.

Areas covered: Our literature search uncovered dozens of industrial and academic patents on the discovery of novel FXIa/FXI inhibitors. Small peptidomimetics, sulfated glycosaminoglycan mimetics, polypeptides, antisense oligonucleotides, and monoclonal antibodies have been developed as inhibitors of FXIa. Although many agents are in early discovery/development phases, the activity and safety of a few have been evaluated in various animal models and in humans.

Expert opinion: FXIa is a promising drug target for development of effective anticoagulants with limited bleeding complications. Literature reveals a major trend in the number of patent applications over the last three years. These inhibitors exploit different approaches for target inhibition. Allosteric modulation of FXIa and biosynthetic inhibition of FXI are mechanistically unique. Despite initial results in patients undergoing knee anthroplasty as with antisense oligonucleotides, major advances should be realized, particularly with respect to pharmacokinetics, for FXI/FXIa inhibitors to enter the clinic.     

A patent review of arginine methyltransferase inhibitors (2010–2018)

Introduction: Protein arginine methyltransferases (PRMTs) are fundamental enzymes that specifically modify the arginine residues of versatile substrates in cells. The aberrant expression and abnormal enzymatic activity of PRMTs are associated with many human diseases, especially cancer. PRMTs are emerging as promising drug targets in both academia and industry.

Areas covered: This review summarizes the updated patented inhibitors targeting PRMTs from 2010 to 2018. The authors illustrate the chemical structures, molecular mechanism of action, pharmacological activities as well as the potential clinical application including combination therapy and biomarker-guided therapy. PRMT inhibitors in clinical trials are also highlighted. The authors provide a future perspective for further development of potent and selective PRMT inhibitors.

Expert opinion: Although a number of small molecule inhibitors of PRMTs with sufficient potency have been developed, the selectivity of most PRMT inhibitors remains to be improved. Hence, novel approaches such as allosteric regulation need to be further studied to identify PRMT inhibitors. So far, three PRMT inhibitors have entered clinical trials, including PRMT5 inhibitor GSK3326595 and JNJ-64619178 as well as PRMT1 inhibitor GSK3368715. PRMT inhibitors with novel mechanism of action and good drug-like properties may shed new light on drug research and development progress.     

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.     

Tyrosyl-tRNA synthetase inhibitors: a patent review

Introduction: Bacterial infection has been a consistent and relentless threat to human health because of emerging resistance to existing antibiotics. Therefore, much of the research has been focused on the design of new potent antibacterial agents. Tyrosyl-tRNA synthetase (TyrRS), as a member of aminoacyl-tRNA synthetase family, could recognize the information including the coincident tRNA molecules and the amino acids’ structures, which are essential in translating the coded information into protein structures in nucleic acids. Therefore, the discovery and application of tyrosyl-tRNA synthetase inhibitors might be a potential strategy to control these diseases in humans.

Areas covered: This review covers 1999 to 2016 wherein several new analogues were claimed as TyrRS inhibitors based on their chemical structures. Xiao, Z.P. et al patented two Chinese patents related to TyrRS inhibitors which are included.

Expert opinion: Due to the pivotal role in translation, tyrosyl-tRNA synthetase has been recognized as a promising target for a new generation of antibiotics with selectivity and specificity. However, while some of the TyrRS inhibitors showed encouraging results, there is an urgent need to develop novel TyrRS inhibitors with higher activity and selectivity. Based on the published SAR results, selective tyrosyl-tRNA synthetase inhibitors could be designed and developed as the next generation of antibacterial agents.     

Platelet-derived growth factor receptor tyrosine kinase inhibitors: a review of the recent patent literature

Importance of the field: Platelet-derived growth factor receptor (PDGFR) is a compelling target for developing therapeutic agents to treat diseases associated with overactivated platelet-derived growth factor (PDGF) signaling and has proved to be particularly encouraging for cancer treatment. The efforts in this area have been greatly enhanced by the approval of tyrosine kinase inhibitors with PDGFR inhibitory activity such as imatinib, sunitinib and sorafenib.

Areas covered in this review: This review surveys the small molecule PDGFR inhibitors reported in patent literature over the past 5 years (2005 – 2009).

What the reader will gain: The reader will gain an overview of the chemical scaffolds and the activity/selectivity of the newly discovered PDGFR inhibitors.

Take home message: Targeting PDGFR kinase with small molecule inhibitors has remained a very active area. Many new and novel PDGFR inhibitors with different selectivity profiles are being discovered and evaluated. In cancer therapy, the identification of novel and potent PDGFR inhibitors with preferred kinase inhibitory profiles that deliver superior antitumor efficacy, yet have manageable side effects and toxicities, will continue to be the key for success. Additionally, interest in targeting PDGF signaling for intervention of various vascular diseases and fibrotic conditions is expected to continue to grow.     

NADPH oxidase inhibitors: a patent review

Introduction: NADPH oxidases, a family of multi-subunit enzyme complexes, catalyze the production of reactive oxygen species (ROS), which may contribute to the pathogenesis of a variety of diseases. In addition to the first NADPH oxidase found in phagocytes, four non-phagocytic NADPH oxidase isoforms have been identified, which all differ in their catalytic subunit (Nox1-5) and tissue distribution.

Areas covered: This paper provides a comprehensive review of the patent literature on NADPH oxidase inhibitors, small molecule Nox inhibitors, peptides and siRNAs.

Expert opinion: Since each member of the NADPH oxidase family has great potential as a therapeutic target, several different compounds have been registered as NADPH oxidase inhibitors in the patent literature. As yet, none have gone through clinical trials, and some have not completed preclinical trials, including safety and specificity evaluation. Recently, small molecule pyrazolopyridine and triazolopyrimidine derivatives have been submitted as potent NADPH oxidase inhibitors and reported as first-in-class inhibitors for idiopathic pulmonary fibrosis and acute stroke, respectively. Further clinical efficacy and safety data are warranted to prove their actual clinical utility.     

Transglutaminase inhibitors: a patent review

Introduction: Transglutaminases (TGases) are a class of enzymes that play multifunctional roles. Their protein-crosslinking activity has been linked to fibrosis and Huntington’s disease, their glutamine deamidation activity has been related to celiac disease and their GTP-binding activity has been implicated in cancer. All of these physiological disorders have prompted the development of inhibitors, which has accelerated dramatically over the past decade.

Areas covered: This review presents an overview of TGase inhibitors published in the patent literature, from the first compounds developed in the late 1980’s, to the current date. This article is focussed on the chemical structure of new inhibitors and their probable mechanism of action.

Expert opinion: Comparison of effective TGase inhibitors reveals common structural features that may guide future design. Many of these elements are embodied in the first TGase inhibitor to recently enter into clinical trials.     

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.     

Selective Tyk2 inhibitors as potential therapeutic agents: a patent review (2015–2018)

Introduction: Tyrosine kinase 2 (Tyk2) is a non-receptor tyrosine-protein kinase, an enzyme that in humans is encoded by the TYK2 gene. Tyk2, together with three other family subtypes, namely, Jak1, Jak2, and Jak3, belong to the JAK family. Before 2014, far more publications and patents appeared in public domain attributing to the development of selective Jak2 and Jak3 inhibitors than those for selective Tyk2 and Jak1 inhibitors.

Areas covered: This review sought to give an overview of patents related to small molecule selective Tyk2 inhibitors published from 2015 to 2018. The article also covers clinical activities of small molecule selective Tyk2 inhibitors in recent years.

Expert opinion: As a key component of the JAK-STAT signaling pathway, Tyk2 regulates INFα, IL12, and IL23. Selective inhibition of Tyk2 can provide pharmacological benefits in the treatment of many diseases such as psoriasis, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), cancer, and diabetes. The selectivity against other Jak family subtypes (such as Jak2) is crucial in order to minimize the potential side effects and to maximize the desired pharmacological effects. In this context, this review of recent selective Tyk2 inhibitor patents may prove valid, interesting, and promising within the therapeutic paradigm.     

Novel nitric oxide synthase inhibitors: a patent review

Introduction: Knowledge of NO and its function in cell signaling has rapidly developed since its biological effects were first described in 1977. It is formed from l-arginine by NOS isoforms (nNOS, iNOS and eNOS). These enzymes are products of separate genes, encoded on three different chromosomes and responsible for regulating a variety of functions within cells and tissues. NOS isoforms are currently under investigation as targets for novel therapeutics in especially neurodegenerative disorders, inflammation and pain. Many important questions regarding these messengers and signaling molecules remain to be answered.

Areas covered: This review gives an overview of patents covering drug-like inhibitors for the NOS isoforms filed and published within the last 6 years, up to September 2010, as well as insight into recent highlights in this area.

Expert opinion: The NOS isoforms are attractive targets in drug design for various pathological conditions and have received considerable interest over recent years. With the advances in molecular biology, modeling software, synthesis, bioassays, and our understanding of the NOS enzymes and the function of NO, novel bioavailable and highly selective drug therapies utilizing this mode of action may soon see the light.     

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.     

Antiobesity carbonic anhydrase inhibitors: a literature and patent review

Introduction: Obesity is ranked as one of the top 10 global health problems and the major concern deriving from it is the exposure of the population to a vast array of chronic pathologies such as cardiovascular and musculoskeletal disorders, type 2 diabetes, cancer, such as colon, breast and endometrial cancer, together with psychological disorders derived from this condition. The discovery that the clinically used anticonvulsants topiramate (TPM) and zonisamide (ZNS) induced weight loss in obese, epileptic patients, afforded the validation of the mitochondrial carbonic anhydrases (CAs, EC 4.2.1.1) VA and VB as targets for the development of antiobesity drugs.

Areas covered: This review deals with the scientific and patent literature regarding obesity or obesity-related pathologies, being particularly focused on the use of carbonic anhydrase inhibitors (CAI) such as TPM and ZNS which inhibit the de novo lipogenesis.

Expert opinion: There is an urgent need of new drugs for the treatment of obesity. The identification that the mitochondrial CAs are implicated in the de novo lipogenesis allowed to consider selective inhibitors of such enzymes as useful for the development of new antiobesity drugs. Actually TPM was approved 1 year ago for this therapy, whereas ZNS is also an effective such agent. These compounds are the lead molecules in this field and an intense research is on the way in order to develop new compounds based on the selective inhibition of mitochondrial CA isoforms.     

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.     

FAK inhibitors in Cancer,a patent review

Introduction: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes at sites of cell adhesion to the extracellular matrix (ECM) and mediates signalling events downstream of integrin engagement of the ECM. FAK is known to regulate cell survival, proliferation and migration.

Areas covered: FAK expression has also been shown to be up-regulated in many cancer types. Previous study also indicates that FAK-mediated signaling and functions are intrinsically involved in the progression of tumor aggressiveness, suggesting that FAK is a promising target for anticancer therapies. Small molecule FAK inhibitors have been developed and are being tested in clinical phase trials.

Expert Opinion: These inhibitors have demonstrated to be effective by inducing tumor cell apoptosis in addition to reducing metastasis and angiogenesis. In this review, we give updates on the design, synthesis and structure-activity relationship analysis of small molecule FAK inhibitors discovered from 2015 until now. We also review the FAK inhibitors that are in clinical development and highlight the future prospects.