Showing papers in "Expert Opinion on Therapeutic Patents in 2018"
TL;DR: Great potential still resides in non-classical CAIs that exhibit alternative binding mechanisms able to further distinguish the various active sites architecture, and CA IX inhibitors hybrids/conjugates are increasingly emerging in the field as promising therapeutic tools to combine CA inhibition to the anticancer effects of other moieties or antitumor drugs.
Abstract: Introduction: Human carbonic anhydrases (CA, EC 4.2.1.1) IX and XII are tumor-associated proteins, being part of the molecular machinery that tumor cells build as adaptive responses to hypoxia and ...
145 citations
TL;DR: This review covers recent efforts in the synthesis and biological screening of quinazoline/quinazolinone based compounds from 2011–2016, and focuses on the promising anticancer activity of qu inazoline and quinzolinone containing compounds.
Abstract: Introduction: Quinazoline and quinazolinone scaffolds represent an important class of biologically active nitrogen heterocyclic compounds. A variety of marketed drugs are based on these moieties. A...
143 citations
TL;DR: This special issue of Expert Opinion on Therapeutic Patents provides an update in these fields, with reviews dedicated to the applications in renal and central nervous system diseases, cancer and metastasis, as well as biomedical applications of prokaryotic CAs, widely abundant in pathogenic bacteria, but also in fungi and protozoa.
Abstract: The metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) is ubiquitously expressed in organisms all over the phylogenetic tree, with seven genetically distinct families known to date. By equilibrating CO2 and bicarbonate with generation of a H + ion, CAs play a crucial role in pH regulation, in providing bicarbonate or H ions for electrolyte secretion, but also in several metabolic pathways such as lipogenesis, gluconeogenesis and ureagenesis. The CA inhibitors (CAIs) are clinically used as diuretics, anti-glaucoma agents and anti-epileptics, but novel applications in the management of cancer, neuropathic pain, sleep apnea, migraine, lowering intracranial pressure, and cerebral ischemia were recently reported. CA activators may be useful in the treatment of cognitive impairment and phobias. This special issue of Expert Opinion on Therapeutic Patents provides an update in these fields, with reviews dedicated to the applications in renal and central nervous system diseases, cancer and metastasis, as well as biomedical applications of prokaryotic CAs, widely abundant in pathogenic bacteria, but also in fungi and protozoa. Some patent evaluations for the use of CAIs in sleep apnea and regulation of mast cell response are also present in this special issue, demonstrating the many new fields in which modulators of the activity of these enzymes may have useful applications. The CAs act as catalysts for the interconversion between CO2, bicarbonate, and protons, one of the simplest chemical reactions connected with vital processes [1–6]. Indeed, CO2, a gas already present in the primeval earth atmosphere, is generated in most oxidative metabolic processes in all organisms (except chemolithoautotrophs), whereas plants use it for photosynthesis. This is probably the reason why at least seven genetically distinct CA families are known to date, being present in organisms all over the phylogenetic tree (denominated as α-, β-, γ-, δ-, ζ-, η-, and ɵ-CAs) [7–15]. A large number of α-CA isoforms have been described in vertebrates: 15 in humans and other primates, and 16 in other mammals [1–6]. Thus, α-CAs are so widespread enzymes probably because their role is connected to tightly controlled processes such as pH regulation and metabolism [1–15]. The view of CAs as metabolic enzymes started to be considered recently, after their role in tumor metabolism has been understood in detail [5,6]. At least CA II, IX, and XII participate in pH regulation and metabolic processes within hypoxic tumors, in which the oxidative phosphorylation of glucose is impaired due to the low amount of oxygen present, and most energy is obtained by the alternative, glycolytic pathway, which leads to the formation of lactic acid [5,6,16–19]. The mitochondrial isoform CA VA was also proven to be involved in biosynthetic processes such as lipogenesis, neoglucogenesis, ureagenesis among others [20–22]. Thus, the clinical use of the CA inhibitors (CAIs) saw new developments in these areas in recent years. The sulfonamides incorporating primary SO2NH2 moieties [23–33] were recognized to act as potent CAIs already in the 1950s, and the first diuretic based on this class of pharmacologic agents, acetazolamide (5-acetamido-1,3,4-thiadiazole2-sulfonamide), started to be clinically used in 1956, with this drug still being used nowadays [1]. In fact, the discovery of acetazolamide played an important role in the development of renal physiology and pharmacology and led to the discovery of many modern classes of diuretics [30–33]. Aspects related to the renal applications of CAIs, alone or in combination with other pharmacological agents, are dealt with in the paper by Supuran in this special issue [34]. Novel applications in the management of drug-induced renal injury were recently reported for classical CAIs such as acetazolamide, methazolamide and topiramate [34], whereas the involvement of renal CA isoforms in the reabsorption of nitrite (NO2 ), which is the most abundant reservoir of the biologically highly potent signaling molecule nitric oxide (NO), has also been investigated in some details in the last years [35,36]. At least 9 of the various CA isoforms are present in the human central nervous system (CNS) and choroid plexus, but their functions are poorly understood, although it is clear that they are involved in crucial functionswithin these organs [34]. CA inhibition in the CNS was exploited therapeutically for obtaining anticonvulsant agents already in the 1970s, with acetazolamide and methazolamide the most used such agents, in some forms of epilepsy [37–39]. The mechanisms by which CAIs exert antiepileptic action are rather complex and there is not a definitive consensus among researchers onmany aspects related to this pharmacological effect of drugs such as topiramate, zonisamide, or sulthiame [37–40]. Inhibition of brain CAs leads to a diminished formation of bicarbonate and also changes the brain pH, contributing thus to an
119 citations
TL;DR: Nutraceuticals represent a challenge for the future of drug-based pharmacotherapy, and, at the same time, are a powerful tool for the prevention of chronic disease.
Abstract: Introduction: In the last 10 years, nutraceuticals have grown in interest to researchers, industry, and consumers and are now familiar in the collective imagination as a tool for preventing...
104 citations
TL;DR: Sulfonamides are utilized as the antiviral HIV protease inhibitor amprenavir, as an anticancer agent, and in Alzheimer’s disease drugs, showing that although known for more than 100 years, the primary sulfonamide constitute an important class of compounds which leads to highly valuable drugs and drug candidates for many conditions.
Abstract: 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 microorgan...
98 citations
TL;DR: Small molecules and peptides targeting PD1/PD-L1 promise to enhance tumor activity while showing less immune related side effects, and potential advantages of small molecules over mAbs include high distribution and better tumor penetration, improved PK/PD, less side effects and oral bioavailability.
Abstract: Introduction: The protein–protein interaction PD1/PD-L1 is an important immune checkpoint and several recently approved monoclonal antibodies show promising anti cancer activities in the clinical practice. However, only a small percentage of cancer patients benefit from PD1/PD-L1 directed mAbs. Moreover, some patients experience immune related side effects upon treatment with these mAbs. Recently, several atomic-resolution structures of human PD1/PD-L1, and small molecules, peptides and mAbs with PD-L1 and PD1 open the field for structure based drug design. Small molecules and peptides targeting PD1/PD-L1 promise to enhance tumor activity while showing less immune related side effects.Areas covered: We reviewed the small molecules classes and peptides targeting PD1/PD-L1.Expert opinion: Currently approved PD1/PD-L1 directed therapeutics show room for improvement. Three classes of non mAb small molecule classes have been discovered so far: (cyclic) peptides as direct competitive PD1/PD-L1 antagonis...
92 citations
TL;DR: New applications were demonstrated in the last years for the CAIs in the management of idiopathic intracranial hypertension, cerebral ischemia, neuropathic pain, avoiding the disruption of blood-brain barrier, and prevention/treatment of migraine, and for the activators for cognition enhancement and the possible treatment of posttraumatic shock and phobias.
Abstract: Introduction: There are tissues and organs, among which kidneys and the central nervous system (CNS), rich in various isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4211) Their role i
91 citations
TL;DR: An overview of the potential use of CAs in biomedical applications, as drug targets, bioindicators, and within artificial organs is presented.
Abstract: Introduction: The hydration/dehydration of CO2 catalyzed by carbonic anhydrases (CAs, EC 4.2.1.1) is a crucial physiological reaction for the survival of all living organisms because it is ...
88 citations
TL;DR: The growing body of patents showed the value of saffron and the respective crucial components alone or in combination with the other raw materials, herbal extracts, to apply in various therapeutic/pharmaceutical areas.
Abstract: Introduction: Saffron and its main components have traditionally been used as pharmaceutical agents. Current experimental research projects have also exhibited their applications in a wide spectrum of disorder treatments.Area covered: This review covers the demonstrated findings and patents on therapeutic/pharmaceutical properties of saffron and related derivatives, since 2000 to bold their outstanding merit on human health. An extensive literature review was performed in USP Patent, Patentscope, Espacenet and Google Patent in the field of CNS, cardiovascular, urogenital, dermatological and inflammatory disorders.Expert opinion: The growing body of patents showed the value of saffron and the respective crucial components alone or in combination with the other raw materials, herbal extracts, to apply in various therapeutic/pharmaceutical areas. They could be engaged as an adjuvant treatment in phototherapy, cancer, cardiovascular and neurodegenerative diseases and hypoxia-induced dangerous conditio...
85 citations
TL;DR: The indazole scaffold is of great pharmacological importance as it forms the basic structure of a large number of compounds with potential therapeutic value and the compounds where mechanism of action is defined can afford new molecules with biological and therapeutic properties.
Abstract: Introduction: Indazoles are heterocyclic moieties rarely found in nature. They are nitrogen containing chemical compounds composed of a pyrazole ring condensed with a benzene ring. Various indazole...
82 citations
TL;DR: New proposed MAO inhibitors are endowed with a marked isoform selectivity, with innovative therapeutic potential toward other targets (gliomas, inflammation, muscle dystrophies, migraine, chronic pain, pseudobulbar affect), and with a promising ability to address multi-faceted pathologies such as Alzheimer’s disease.
Abstract: Introduction: Monoamine oxidase (MAO) inhibitors, after the initial ‘golden age’, are currently used as third-line antidepressants (selective MAO-A inhibitors) or clinically enrolled as co-adjuvant...
TL;DR: α-MG can be a promising drug, also worthy of developing, and further research is crucial for the future application of α-MG, which has the effect of maintaining cardiovascular system and gastrointestinal health and controlling free radical oxidation.
Abstract: Introduction: α-Mangostin (α-MG) is the most representative xanthone isolated from the pericarp of mangosteen, possessing extensive biological activities and pharmacological properties, considered as an antineoplastic agent, antioxidant, anti-proliferation and induces apoptosis.Areas covered: The bioactivity and pharmacological properties of α-MG are being actively investigated by various industrial and academic institutions. The bioactivities of α-MG have been summarized in several previous reviews, which were worthy of high compliment. However, recently, many new literatures about the bioactivities of α-MG have been further reported from 2016 to 2017. Herein, the activities of α-MG are supplemented and summarized in this text.Expert opinion: As previously said, α-MG possesses good bioactivities pharmacological properties. More recently, it found that α-MG has the effect of maintaining cardiovascular system and gastrointestinal health and controlling free radical oxidation. Furthermore, α-MG has ...
TL;DR: This review demonstrates that the structural diversity of new IDO1 inhibitors could be expanded via a number of approaches and provides insights for inhibitor-enzyme interactions and guidance for the design and discovery of next generation inhibitors.
Abstract: 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-en...
TL;DR: 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 i...
Abstract: 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 i...
TL;DR: In the last 10 years, a broad spectrum of applications in medicinal chemistry have been proposed due to its physicochemical properties and properties, such as its ability to be used in a wide range of applications.
Abstract: Introduction: Benzoxaborole is a versatile boron-heterocyclic scaffold which has found in the last 10 years a broad spectrum of applications in medicinal chemistry, due to its physicochemical and d...
TL;DR: Despite the significant number of patent applications claiming steroidal and non-steroidal FXR agonists, several questions on their therapeutic potential in cholestasis and NASH remain open leaving a space for the development of novel compounds.
Abstract: Introduction. The nuclear receptor FXR regulates the expression of genes involved in bile acids, glucose and lipid homeostasis. For its role as guardian of metabolism, FXR has been identified a pro...
TL;DR: UA and its analogs (to a greater extent than UA) can be useful in cancer drug treatment and have the potential for joint application with other anticancer drugs in order to overcome drug resistance.
Abstract: Introduction: Usnic acid (UA) is a lichen-derived secondary metabolite with a unique dibenzofuran skeleton and is commonly found in lichenized fungi of the genera Usnea and Cladonia. Usnic acid has been incorporated for years in cosmetics, perfumery, and traditional medicines. It has a wide range of bioactivities, including antimicrobial, antiviral, anticancer, anti-inflammatory properties.Areas covered: This review covers patents on therapeutic activities of UA and its synthetic derivatives published during the period 2000–2017.Expert opinion: UA demonstrates excellent anticancer and antimicrobial properties. However, its application was withdrawn due to acute liver toxicity reported with chronic consumption. The broad spectrum of its biological activity indicates high the variability of UA’s binding preferences. The main idea to be addressed in the future should include the synthesis of UA derivatives because these might possess increased bioactivity, bioavailability and decreased toxicity. It i...
TL;DR: The present review seeks to summarize published patent applications from assignee companies that have disclosed direct small molecule inhibitors of the YAP/TAZ–transcriptional enhanced associate domain (TEAD) interaction to generate the first clinical stage inhibitor of the Hippo pathway.
Abstract: Introduction: The Hippo pathway represents a new and intriguing opportunity for the treatment of cancer. Activation or overexpression of Yes-associated protein (YAP) or transcriptional coactivator ...
TL;DR: This review provides an update on the development of FXR modulators for enterohepatic diseases and offers an in-depth perspective on new strategies for the developmentof novel FXRmodulators.
Abstract: Introduction: Farnesoid X receptor (FXR), a nuclear receptor mainly expressed in enterohepatic tissues, is a master for bile acid, lipid and glucose homeostasis. Additionally, it acts as a ...
TL;DR: It is noteworthy that the C-30 amide of GA demonstrated better cytotoxic effects compared to the parent compounds, which is expected to stimulate medicinal chemist to synthesize new lead compounds in cancer drug discovery.
Abstract: Introduction: Glycyrrhetinic acids (GAs) viz., 18β-glycyrrhetinic acid and 18α-glycyrrhetinic acid, are oleanane-type triterpenes having a carboxylic acid group at C-30, and are extracted f...
TL;DR: This review summarizes the recent advances in small molecule inhibitors of E1s, E2s, and E3s, with a focus on the latest patents (from 2015 to 2018) of E3 inhibitors and modulators.
Abstract: Introduction: Ubiquitin-proteasome system (UPS) has been validated as a novel anticancer drug target in the past 20 years. The UPS contains two distinct steps: ubiquitination of a substrate protein...
TL;DR: QS inhibition can reduce the virulence of bacteria without affecting their growth or killing them and the reduced pressure may minimize the increasingly resistance.
Abstract: Introduction: Quorum sensing (QS) is a cell density-dependent phenomenon in which specific pathways are activated after autoinducers (AIs) outside the microorganism reach a threshold concentration. QS creates a positive feedback loop that induces a cascade of gene expression and causes biofilm formation, virulence and sporulation. QS signals are diverse, acyl-homoserine lactone (AHL), AI peptide (AIP) and AI-2 are three major categories of QS signals. QS inhibitors (QSIs) can disrupt or prevent the formation of biofilm and reduce virulence while exerting less selective pressure on the bacteria, suggesting that QSIs are potential alternatives for antibiotics. Areas covered: This review summarized the pertinent patents on QS inhibition available from 2014 to 2018. The authors analyze these patents and provided an overview of them and their potential applications. Expert opinion: The main strategy for QS inhibition is to use the analogues of various QS signals to block downstream signal transducers. The inactivation of signal molecules or the stimulation of the immune response is also attractive strategies to inhibit QS. However, additional clinical trials are needed to assess their efficacy in mammals. In sum, QS inhibition can reduce the virulence of bacteria without affecting their growth or killing them and the reduced pressure may minimize the increasingly resistance.
TL;DR: For effective clinical application of caspase inhibitors, novel peptidic and nonpeptidic caspases with lower toxicity and improved efficacy should be developed via structural modifications, and further animal studies and preclinical and clinical trials are needed.
Abstract: Introduction: Although many caspase inhibitors have been patented, caspase inhibitors have not entered the market due to their toxicity and poor pharmacokinetic profile.Areas covered: In this article, we review patents (2013–2015) for peptide and non-peptide caspase inhibitors and their compositions.Expert opinion: Noteworthy patents include a peptidic caspase-2 inhibitor for nasal administration and a peptidomimetic caspase-6 inhibitor that can be administered via several routes for the treatment of neurodegenerative diseases. Furthermore, caspase-1 inhibitors for contact dermatitis and inflammation, cardiovascular diseases, and liver diseases and a caspase-3 inhibitor for cerebral stroke have been patented. Of particular interest is the novel use of tyrosine kinase inhibitors (sunitinib and its derivatives) for the prevention and treatment of age-related ocular diseases via inhibition of the caspase-3, dual-leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) pathways. However, fo...
TL;DR: The present review covers patent literature on serine protease inhibitors for the therapy of inflammatory diseases patented between 2011 and 2016 and finds a significant number of patents are related to retinal vascular dysfunction and skin diseases.
Abstract: 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, bl...
TL;DR: Current medicinal chemistry strategies are inadequate, and appropriate and new methodologies and technologies should be exploited to identify novel anti-HIV drug candidates in a time- and cost- effective manner.
Abstract: Introduction: To deal with the rapid emergence of drug resistance challenges, together with the difficulty to eradicate the virus, off-target effects and significant cumulative drug toxicities, it ...
TL;DR: Compared with traditional diagnostic tools, circulating miRNAs have many strongpoints, suggesting that circulating mi RNAs can serve as promising biomarkers for the early diagnosis and prognosis of CAD.
Abstract: Introduction: Coronary artery disease (CAD) contributes to a huge number of human death worldwide. The early diagnosis can arrest the development of CAD and effectively lower the mortality ...
TL;DR: Increasing evidence supports BuChE as a more beneficial target in moderate-to-severe forms of AD in comparison to the well-known AChE, however, hitting a single pathological target is likely not sufficient to halt the disease progression.
Abstract: Introduction Butyrylcholinesterase (BuChE) has obtained a renewed interest as therapeutic target in Alzheimer's disease (AD), when changes in BuChE activity and expression along disease progression were highlighted as well as correlation between BuChE levels and cognitive function. Areas covered During the last eight years, fourteen patents on BuChE inhibitors (BuChEI) have been submitted. Only three of them relate to BuChE selective inhibitors, while four of them focus on multitarget inhibitors which address different key pathological factors other than BuChE. Two patents report on non-selective acetylcholinesterase (AChE)/BuChE inhibitors, while four patents deal with natural compounds and their derivatives. One patent relates to antitoxic agents to treat exposure to ChEI pesticides and nerve agents. Expert opinion Increasing evidence supports BuChE as a more beneficial target in moderate-to-severe forms of AD in comparison to the well-known AChE. However, hitting a single pathological target is likely not sufficient to halt the disease progression. Therefore, patented BuChE inhibitors with a multifunctional profile may open new therapeutic avenues, since the additional activities could reinforce the therapeutic effects. Unfortunately, in vivo studies are limited and key parameters, such as ADMET data, are missing. This lack of information makes difficult to forecast the development of patented BuChEIs into effective drug candidates.
TL;DR: First results from clinical trials have verified potential utility of histamine H3R antagonist/inverse agonists in some diseases, but more studies are necessary for better understanding of an involvement of the histaminergic system in CNS-related disorders and helping more ligands approach to clinical trials and the market.
Abstract: Introduction: Since years, ligands blocking histamine H3 receptor (H3R) activity (antagonists/inverse agonists) are interesting targets in the search for new cures for CNS disorders. Intensive works done by academic and pharmaceutical company researchers have led to many potent and selective H3R antagonists/inverse agonists. Some of them have reached to clinical trials.Areas covered: Patent applications from January 2013 to September 2017 and the most important topics connected with H3R field are analysed. Espacenet, Patentscope, Pubmed, GoogleScholar or Cochrane Library online databases were principially used to collect all the materials.Expert opinion: The research interest in histamine H3R field is still high although the number of patent applications has decreased during the past 4 years (around 20 publications). Complexity of histamine H3R biology e.g. many isoforms, constitutive activity, heteromerization with other receptors (dopamine D2, D1, adenosine A2A) and pharmacology make not easy re...
TL;DR: The present review gives an overview of the patent literature over the period 1994–2017 of different immunoglobulin gamma-based bispecific antibody platforms and the molecules approved or in clinical trials.
Abstract: Introduction: Bispecific antibodies have become increasingly of interest by enabling new therapeutic applications such as retargeting cellular immunity towards tumor cells. About 23 bispecific anti...
TL;DR: The flexible nature of this ligand for various molecular level targets (enzyme/receptor) make this heterocylce an attractive scaffold for development of effective and clinically relevant oxazole containing therapeutic agents.
Abstract: Introduction: Oxazoles are oxygen and nitrogen containing five membered heterocyclic ring systems that are present in various anticancer, antimicrobial, antihyperglycemic, anti-inflammatory agents