Expert Opinion on Therapeutic Patents

Publications in this journal

• Article: Favourable changes to the IP and tax systems in the UK for drug development.

  Robert Watson
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  ABSTRACT: The editorial discusses the planned introduction into U.K. patent law of a new exemption from patent infringement for all activities required to secure regulatory approval to market innovative drugs, which brings the UK into line with other major European jurisdictions. It is also planned to exempt studies carried out in relation to reimbursement work. These new exemptions, when set alongside the recent impletion of the Patent Box, offering a reduction in corporation tax on profits earned from patents and Research and Development tax relief, show how the UK Government is trying to make good on its promise to ensure the UK is a leader in Life Sciences Innovation.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: Estrogen receptor ligands: a patent review update.

  Ilaria Paterni, Simone Bertini, Carlotta Granchi, Marco Macchia, Filippo Minutolo
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  ABSTRACT: Introduction: The role of estrogens is mostly mediated by two nuclear receptors (ERα and ERβ) and a membrane-associated G-protein (GPR30 or GPER), and it is not limited to reproduction, but it extends to the skeletal, cardiovascular and central nervous systems. Various pathologies such as cancer, inflammatory, neurodegenerative and metabolic diseases are often associated with dysfunctions of the estrogenic system. Therapeutic interventions by agents that affect the estrogenic signaling pathway might be useful in the treatment of many dissimilar diseases. Areas covered: The massive chemodiversity of ER ligands, limited to patented small molecules, is herein reviewed. The reported compounds are classified on the basis of their chemical structures. Non-steroidal derivatives, which mostly consist of diphenolic compounds, are further segregated into chemical classes based on their central scaffold. Expert opinion: Estrogens have been used for almost a century and their earlier applications have concerned interventions in the female reproductive functions, as well as the treatment of some estrogen-dependent cancers and osteoporosis. Since the discovery of ERβ in 1996, the patent literature has started to pay a progressively increasing attention to this newer receptor subtype, which holds promise as a target for new indications, most of which still need to be clinically validated.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: Adenosine A1 modulators: a patent update (2008 to present).

  Irene Giorgi, Paola Nieri
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  ABSTRACT: Introduction: In 2008, we published our review titled 'Therapeutic potential of A1 adenosine receptor ligands - a survey of recent patent literature' that reported the compounds active on A1 adenosine receptors (ARs) and the applications of A1 AR ligands patented in the period 2005 - 2008. Areas covered: This article is a discussion of the patents about the same subjects, issued in the period 2008 to present. It is organized similarly to the first one, with a section about new compounds, subdivided on the basis of their functional activity (agonists, antagonists and allosteric modulators) and a section regarding new therapeutic applications. Expert opinion: The main novelty is represented by the patenting of A1 AR ligands with dual selectivity which may show, in some conditions, better efficacy and fewer side effects. Moreover, while the way to arrive into the market appears full of obstacles for selective A1 ligands that need systemic administration for long-term therapy, better chances are foreseen in applications requiring topical administration.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: Antagonists of IL-1R: a patent evaluation (WO2012122985).

  Claudio Sette
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  ABSTRACT: IL-1 is a master cytokine that plays a pivotal role in local and systemic inflammation and is involved in the host response to both physiological and pathological stimuli. The recent development of biological compounds targeting IL-1 activity in vivo has revealed the contribution of this cytokine to a large number of human inflammatory and autoimmune diseases. Nevertheless, these currently used drugs display some disadvantages that limit their use in several IL-1-driven diseases, urging for the identification of more powerful agents. The present article describes the identification of new small peptides displaying IL-1 inhibitory activity and covered by the patent WO2012122985. The experimental work in support of the patent's claims is also discussed. Specific attention is paid to the comparison with the original compound from which the peptides were originated: the IL-1 receptor antagonist (IL-1RA) protein. The potential advantages brought about by the present invention as well as the limits documented by the experimental results shown in the patent are also discussed.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: Non-peptidic δ opioid receptor agonists and antagonists (2000 - 2012).

  Hideaki Fujii, Toshihiro Takahashi, Hiroshi Nagase
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  ABSTRACT: Introduction: The δ opioid receptor mediates various pharmacological effects such as antinociceptive and antidepressant effects, whereas it does not appear to induce μ opioid-like side effects such as dependence, respiratory depression and constipation. Therefore, the δ opioid receptor is a promising drug target. Areas covered: This review covers literature and patents concerning non-peptidic δ opioid receptor agonists, antagonists, modulators and ligands from 2000 to 2012. Pharmacological effects induced by δ receptor agonists or antagonists are also discussed. Expert opinion: Potential therapeutic effects by δ receptor agonists are antinociceptive, antidepressant, anxiolytic, cardioprotective and neuroprotective effects. Among them, anxiolytic effects are of particular interest because the anxiolytic effects by a δ receptor agonist have been observed in humans. Although non-peptidic δ receptor agonists were reported to show convulsive effects via the δ opioid receptor, some δ receptor agonists are known to produce no convulsive behaviors. Therefore, it may be possible to eliminate convulsion induced by a δ receptor agonist. Many δ receptor antagonists were also reported but there is little new information about pharmacological effects by a δ receptor antagonist. Although detailed results were not revealed, two δ receptor antagonists with μ receptor agonistic or antagonistic properties are in the late stages of the clinical trial.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: Benzofuran derivatives: a patent review.

  Kamal M Dawood
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  ABSTRACT: Introduction: Benzofuran moiety constitutes the core of several interesting pharmacologically active natural products. Benzofurans are among feasible potent active inhibitors against many diseases, viruses, microbes, fungus and enzymes. Several series of therapeutically important synthetic and naturally occurring benzofuran-containing compounds are reported in this chapter. Areas covered: The current chapter focuses on the recent applications of benzofuran scaffolds and their wide range of biological activities during 1999 - 2012. The pharmacological areas covered included anti-inflammatory, antitumor, cytotoxic, antimicrobial, antitubercular, antioxidant, antiplasmodial, trypanocidal and insecticidal activities as well as enzyme inhibitory, HCV and HIV inhibitory activities. Expert opinion: The results reported in the chapter indicate that some benzofuran derivatives may be useful as potent drugs. From the structure-activity relationship (SAR), the presence of certain functions like -OH, -OMe in the benzofuran derivatives contributed greatly in increasing the potency of their therapeutic activities when compared with standards. For example, presence of the -OH and -OMe have made some benzofuran compounds more potent HIV-RT inhibitory activity than the standard atevirdine, and more potent antitumor agent when compared with standards (fluorouracil, doxorubicin and cytarabine). In addition, the enzyme aromatase CYP19 inhibitory activity of benzofurans having -OH and -OMe were greater than that observed for the reference arimidex.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: New substituted benzimidazole derivatives: a patent review (2010 - 2012).

  Fan Fei, Zhiming Zhou
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  ABSTRACT: Introduction: Benzimidazole is a heterocyclic aromatic system, which is part of some natural and many synthetic compounds. A large number of benzimidazoles and its derivatives are found to be biologically active against many diseases. Researchers around the world are paying greater attention to and showing increasing interests in this field. Areas covered: Areas covered in this paper include a review of the synthesis, biological effects and mechanisms of benzimidazole derivatives in the past 2 years, based on literature and patents. The patent databases SciFinder and esp@cenet were used to locate patent applications that were published between 2010 to present. Information from articles published is also included. The current state and problems are also discussed. Expert opinion: Benzimidazole derivatives possess a broad spectrum of biological activities, whose scopes of treatment ranging from ordinary antimicrobial activities to world's most deadly diseases. However, challenges such as drug resistance, relatively little knowledge of structure of receptors and rare convenient methods for synthesis of benzimidazoles still exist.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: Anticancer carbonic anhydrase inhibitors: a patent review (2008 - 2013).

  Simona Maria Monti, Claudiu T Supuran, Giuseppina De Simone
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  ABSTRACT: Introduction: Human carbonic anhydrases (EC 4.2.1.1) IX (hCA IX) and XII (hCA XII) are two tumor-associated proteins, being overexpressed in many tumors and involved in critical processes associated with cancer progression and response to therapy. Both are multi-domain proteins consisting of an extracellular catalytic domain (CA), a transmembrane portion (TM) and an intracytoplasmic (IC) segment. These domains have peculiar biochemical and physiological features. CA IX contains an additional proteoglycan-like (PG) domain at the N-terminus which constitutes a unique feature of this enzyme within the CA family. Areas covered: Starting from a brief description of the main molecular and catalytic features of both enzymes, their role in tumor physiology and their three-dimensional structure, this review describes the main classes of small molecule inhibitors, investigated between 2008 and 2013, able to inhibit these enzymes for both diagnostic and therapeutic applications. Expert opinion: A consistent number of patents on molecules able to inhibit the catalytic activity of CA IX and CA XII have been recently reported. Most patents deal with classical sulfonamide derivatives, demonstrating that introducing suitable substituents on the inhibitor scaffold, good selectivity can be obtained. However, the most impressive results are related to compounds containing novel chemotypes, such as coumarins and thiocumarins. Thus, it is expected that research in next future will be more dedicated to the development of molecules containing new chemotypes and a large number of studies in such field have already been published demonstrating the role of these enzymes in carcinogenesis and metastases formation.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: Substituted oxadiazoles: a patent review (2010 - 2012).

  Afshin Zarghi, Zahra Hajimahdi
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  ABSTRACT: Introduction: The oxadiazoles represent a class of five-membered heterocyclic compounds which are of considerable interest in different areas of medicinal chemistry and drug discovery. Oxadiazoles can exist in different regioisomeric forms and employ in various agents with a broad range of biological activities. This review covers the work reported on various biological activities of oxadiazole derivatives from 2010 to 2012. Areas covered: Oxadiazole derivatives attract great attention due to their different kinds of pharmaceutical activities including antiviral, antimicrobial, anticancer, anticonvulsant, antidiabetic and anti-inflammatory activity. This paper provides a general review of oxadiazole derivatives published in international journals and patented between 2010 and 2012. Expert opinion: Oxadiazoles have been used frequently in drug-like molecules as bioisosteres for ester and amide functionalities and displayed numerous prominent pharmacological effects. The broad pharmacological profile of oxadiazole derivatives has attracted the attention of many researchers to explore this scaffold to its multiple potential against several activities. Therefore, oxadiazole motif is likely to be present in other therapeutic molecules in the future.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: Recent development on naphthoquinone derivatives and their therapeutic applications as anticancer agents.

  Vishnu Kumar Tandon, Sandeep Kumar
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  ABSTRACT: Introduction: A large number of natural products including several synthetic drugs possess naphthoquinone chromophore. Various methods have been devised for their synthesis. Several naphthoquinone derivatives have been found to possess diverse biological properties especially anticancer activity which has stimulated keen interest and research in this field. Areas covered: The present review provides recent therapeutic patent literature (2000 - 2012) describing the applications of naphthoquinones and their derivatives on anticancer activities. Information from articles published in international peer-reviewed journals has been included to comprise a more exhaustive review. Expert opinion: With the advent of stem cell research and molecular mechanism associated with cure of cancer, the use of classical and novel naphthoquinone structures have been more frequently noted in recent (2000 - 2012) patented agents for treatment of cancer.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: Autotaxin inhibitors: a patent review.

  Efrosini Barbayianni, Victoria Magrioti, Panagiota Moutevelis-Minakakis, George Kokotos
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  ABSTRACT: Introduction: Autotaxin (ATX) is a lysophospholipase D enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA) and choline. LPA is a bioactive lipid mediator that activates several transduction pathways, and is involved in migration, proliferation and survival of various cells. Thus, ATX is an attractive medicinal target. Areas covered: The aim of this review is to summarize ATX inhibitors, reported in patents from 2006 up to now, describing their discovery and biological evaluation. Expert opinion: ATX has been implicated in various pathological conditions, such as cancer, chronic inflammation, neuropathic pain, fibrotic diseases, etc. Although there is an intensive effort on the discovery of potent and selective ATX inhibitors in order to identify novel medicinal agents, up to now, no ATX inhibitor has reached clinical trials. However, the use of ATX inhibitors seems an attractive strategy for the development of novel medicinal agents, for example anticancer therapeutics.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: Discovery and development of heat shock protein 90 inhibitors as anticancer agents: a review of patented potent geldanamycin derivatives.

  Taehun Kim, Gyochang Keum, Ae Nim Pae
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  ABSTRACT: Introduction: There has been research on anticancer strategies which focus on disrupting a single malignant protein. One of the strategies is the inhibition of one protein, heat shock protein 90 (Hsp90). There are many reasons why Hsp90 protein is targeted by anticancer agents: maintenance of cellular homeostasis in organisms involves Hsp90 and its client proteins; moreover, Hsp90 complex is involved in regulating several signal transduction pathways and plays an important role in the maturation of lots of tumor-promoting client proteins. Geldanamycin (GM), the first benzoquinone ansamycin, has shown anticancer activity by binding to Hsp90. Currently, several GM derivatives such as 17-AAG, 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin, IPI-493, and IPI-504 are being progressively developed toward clinical application. Areas covered: Several research groups have studied GM and its derivatives to develop novel and potent Hsp90 inhibitors for the treatment of cancer. The crystal structure of Hsp90 was utilized to undergo structural optimization of GM derivatives. A wide variety of structural modifications were performed and some of the derivatives are now in clinical studies. The aim of this review was to summarize and analyze the structure-activity relationships of GM derivatives and the focus is on patented novel and pharmaceutically efficacious derivatives published from 1971 to 2012. Expert opinion: Hsp90 inhibitors offer an effective therapeutic approach for treatment of cancer. To date, the clinical results of 17-AAG, IPI-493, and IPI-504 suggest that these GM derivatives could be used either alone or in combination with other marketed medications for the treatment of cancer patients. As there are not any marketed Hsp90 inhibitors, inhibiting Hsp90 chaperone function remains as a promising strategy that still requires further research.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: Phosphodiesterase-4 inhibitors: a review of current developments (2010 - 2012).

  Amadeu Gavaldà, Richard S Roberts
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  ABSTRACT: Introduction: At last, after many years of research, roflumilast has become the first oral phosphodiesterase-4 inhibitor to be approved by the medical agencies as an add-on therapy for chronic obstructive pulmonary disease. A second compound, apremilast is targeted for submission of new drug application for the treatment of psoriasis in the second half of 2013. These compounds represent a breakthrough and a reward in the field after the many failures to date in clinical development. Areas covered: This review summarizes the clinical development of PDE4 inhibitors from 2010 - 2012 and the associated patent literature with a focus on strategies to overcome the common pitfalls of oral PDE4 inhibitors. Expert opinion: In the last few years, influenced by the body of published clinical data, many companies have lost interest in PDE4 as a target. Many of those that have persevered have opted to realign their research programs either toward compounds specifically designed for inhaled delivery or in search of an increase in clinical efficacy by combining two mechanisms in a single compound. This change is reflected by the continued disclosure of novel and chemically diverse molecules, indicating for some in the pharmaceutical industry that all is not yet lost.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: Corticotropin-releasing factor 1 receptor antagonists: a patent review.

  John P Williams
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  ABSTRACT: Introduction: Corticotropin-releasing factor (CRF) is a 41 amino acid peptide hypothalamic factor that plays a key role in the body's response to stress. The receptors for CRF (CRF1 and CRF2) are members of the class B G-protein coupled receptor family and several small molecule antagonists have been evaluated clinically in stress-related disorders. Areas covered: The present review covers the disclosures of non-peptide CRF1 antagonists in the patent literature since 2006. Expert opinion: Antagonists of the CRF1 receptor have failed to demonstrate clinical utility. All of the compounds evaluated are similar structures and are allosteric inhibitors of the CRF1 receptor. Further clinical evaluation of new compounds appears unlikely unless novel structures are identified that interact with the receptor distinct to the first-generation antagonists.
  Expert Opinion on Therapeutic Patents 05/2013;
• Article: Antiglaucoma carbonic anhydrase inhibitors: a patent review.

  Emanuela Masini, Fabrizio Carta, Andrea Scozzafava, Claudiu T Supuran
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  ABSTRACT: Introduction: Glaucoma is one of the major causes of blindness, affecting together with age-related macular degeneration > 70 million people worldwide. One of the therapeutic options for its management is based on the inhibition of the metalloenyme carbonic anhydrase (CA, EC 4.2.1.1). CA inhibitors (CAIs) diminish intraocular pressure (IOP) by reducing the rate of bicarbonate formation and thus secretion of the aqueous humor. Areas covered: The main classes of clinically used antiglaucoma CAIs are the sulfonamides with systemic (acetazolamide, methazolamide, ethoxzolamide and dichlorophenamide) and topical (dorzolamide and brinzolamide) action. A patent literature review covering the period 2007 - 2013 is presented. Expert opinion: This review presents an overview of the patent literature in the CAI antiglaucoma drug design field during the past 6 years. Most of the patents deal with sulfonamide/sulfamide/sulfamate CAIs, sulfonamides incorporating NO-donating moieties, as well as hybrids incorporating sulfonamide and prostaglandin (PG) analogs, were also reported. There is an urgent need for new antiglaucoma CAIs/approaches to treat and diagnose this disease in the very near future, as the last drug which has been discovered in the field (latanoprost) dates back > 10 years ago.
  Expert Opinion on Therapeutic Patents 04/2013;
• Article: Glycogen phosphorylase inhibitors: a patent review (2008 - 2012).

  Nicolas Gaboriaud-Kolar, Alexios-Leandros Skaltsounis
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  ABSTRACT: Introduction: Glycogen phosphorylase (GP) is the enzyme responsible for the synthesis of glucose-1-phosphate, the source of energy for muscles and the rest of the body. The binding of different ligands in catalytic or allosteric sites assures activation and deactivation of the enzyme. A description of the regulation mechanism and the implications in glycogen metabolism are given. Areas covered: Deregulation of GP has been observed in diseases such as diabetes mellitus or cancers. Therefore, it appears as an attractive therapeutic target for the treatment of such pathologies. Numbers of inhibitors have been published in academic literature or patented in the last two decades. This review presents the main patent claims published between 2008 and 2012. Expert opinion: Good inhibitors with interesting IC50 and in vivo results are presented. However, such therapeutic strategy raises questions and some answers are proposed to bring new insights in the field.
  Expert Opinion on Therapeutic Patents 04/2013;
• Article: Biological activities of guanidine compounds, 2008 - 2012 update.

  Franciszek Sączewski, Lukasz Balewski
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  ABSTRACT: Introduction: Compounds incorporating guanidine moiety have found many practical applications in diverse areas of chemistry, such as nucleophilic organocatalysis, anion recognition and coordination chemistry. Moreover, guanidine functional group is found in natural products, pharmaceuticals and cosmetic ingredients produced by synthetic methods. Thus, knowledge of their biological activities and therapeutic uses is of utmost importance for researchers involved in drug discovery processes. Areas covered: In this review the authors highlight the continued development and therapeutic applications of newly synthesized guanidine-containing compounds including small peptides and peptidomimetics incorporating arginine. The review presents patents and patent applications filed in the years 2008 - 2012 with emphasis placed on new mechanisms of pharmacological action of guanidine derivatives. Expert opinion: While guanidines are often thought of as strong organic bases and compounds hydrophilic in nature, over the last 4 years there has been an enormous increase in discovery of new promising lead structures with guanidine core, suitable for development of potential drugs acting at central nervous system, anti-inflammatory agents, anti-diabetic and chemotherapeutic agents as well as cosmetics.
  Expert Opinion on Therapeutic Patents 04/2013;
• Article: Topoisomerase inhibitors as anticancer agents: a patent update.

  Daulat B Khadka, Won-Jea Cho
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  ABSTRACT: Introduction: Topoisomerases (topos) are nuclear enzymes that resolve topological problems associated with DNA during various genetic processes. The essential role of topos in vital processes of the cell, their elevated level in solid tumors and cell death due to their inhibition make topos inhibitors as a potent class of antineoplastic agents. Areas covered: This review specifically summarizes patents embracing topo I, topo I and II inhibitors. The review covers topos inhibitors which are structurally close to camptothecin (CPT), natural products such as lamellarins and synthetic trisubstituted pyridines. It largely focuses on chemical entities developed by systematic structure-activity relationship (SAR) studies of natural benzo[c]phenanthridine (nitidine) and synthetic protoberberine (coralyne) established as antineoplastic agents targeting topo(s). In addition, indenoisoquinolines and evodiamines initially discovered through COMPARE analysis and receptor-based virtual screening (VS) respectively have been discussed. Expert opinion: Along with conventional techniques, computer-aided VS, molecular modeling and docking studies have been applied for drug design, discovery and development. Computer-aided tools provide a rational way to explain pharmacological activities of topos inhibitors under study. Comparative study of crystal structures of topo I/II-DNA-drug ternary complex and use of appropriate pharmacological screening methods will lead to potential anticancer drugs in the coming days.
  Expert Opinion on Therapeutic Patents 04/2013;
• Article: Antiobesity carbonic anhydrase inhibitors: a literature and patent review.

  Andrea Scozzafava, Claudiu T Supuran, Fabrizio Carta
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  ABSTRACT: 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.
  Expert Opinion on Therapeutic Patents 04/2013;