Expert Opinion on Therapeutic Patents最新文献

Introduction: Tuberculosis (TB) remains a major global health issue, causing around 10 million new cases and 1.3 million deaths in 2022. The challenge is compounded by multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB strains, and co-infection with HIV.

Areas covered: The present review examines significant patent literature on TB chemotherapeutics from September 2021 to the present using the following databases, reaxys, google patent and espacenet. Only patents reporting compounds with a minimum inhibitory concentration (MIC) on whole Mycobacterium tuberculosis cells of ≤5 µM were selected for review.

Expert opinion: The fight against TB is advancing with the development of promising new compounds due to the challenge of drug-resistant strains. Notable among those reviewed in this paper are the benzothiazinones, showing high efficacy against both drug-sensitive and resistant TB strains. Additionally, Q203 analogues, demonstrate strong antitubercular activity, good microsomal stability, and favorable safety profiles. Finally, LysRS inhibitors also show significant promise in vivo models. These advancements underscore the importance of novel targets and innovative strategies in developing effective, resistance-resistant TB treatments.

Introduction: Helicobacter pylori infects almost half of the World population. Although many infected people are symptom free, the microorganism can still cause a variety of gastrointestinal disorders and gastric adenocarcinoma. It is considered a priority pathogen for the development of new antibiotics by the World Health Organisation (WHO). Many virulence factors of H. pylori have been described. This paper will on H. pylori Urease (HPU).

Area covered: This paper will discuss the (patho)physiology and structure of HPU. In addition, urease inhibitors with known activity against the HPU or inhibitors that show H. pylori growth inhibition will be discussed.

Expert opinion: Increase in selectivity, affinity and potency of HPU inhibitors can be achieved by the design of compounds that interact with distinct regions within the enzyme active site. Especially, covalent interactions seem promising as they clearly effect the dose requirement of the drug candidate.

Introduction: UNC-51-like kinase 1/2 (ULK1/2) are serine/threonine kinases that play a crucial role in autophagy activation and maintaining cellular homeostasis. Given their broad physiological relevance, ULK1/2 are candidate targets for treating various diseases. In recent years, ULK1/2 inhibitors have made significant progress, and the highly potent ULK1/2 inhibitors have entered clinical trials.

Area covered: This review aims to provide an updated analysis of patents describing ULK1/2 inhibitors and their potential therapeutic applications that were disclosed between 2019 and 2024.

Expert opinion: Due to their crucial role in various diseases, the invention of small-molecule drugs targeting ULK1/2 is particularly important, especially in cancer treatment. Despite the great success of ULK1/2 inhibitors development, ULK1/2 inhibitors are ATP competitive inhibitors of aminopyrimidines currently, and most ULK1/2 inhibitors are still in the preclinical research stage, with only DCC-3116 entered clinical research. Therefore, developing highly selective ULK1/2 inhibitors with low side effects and high bioavailability remains a challenging and promising research direction.

Introduction: Acute leukemia harboring rearrangement of the Mixed lineage leukemia (MLL) and/or mutation of the nucleophosmin is a type of poorly prognostic and highly malignant leukemia which is extremely difficult to treat. Blocking the protein-protein interaction between Menin and MLL is a strategic approach for treating leukemias, as a new direction for drug discovery. Many biotech and pharmaceutical companies made great efforts to this drug development field, and a large number of small molecular Menin-MLL PPI inhibitors were reported during the recent three years.

Areas covered: This review is to mainly summarize the Menin-MLL PPI inhibitors reported in the recent three years' patents.

Expert opinion: Although the past 12 years have witnessed the progress of the Menin-MLL PPI inhibitors in the treatment of acute leukemia, especially for leukemia harboring rearranged KMT2A and/or mutated NPM1, recent studies showed Menin-MLL PPI inhibitors suffered from new issues such as toxicity, acquired resistance, and homogenization. Therefore, new drug discovery strategies should be considered in advance. The expert opinion was proposed from several aspects, such as developing diverse chemical structures, discovering covalent inhibitors, designing small molecular PROTACs, and targeting the amino acids mutations for next-generation inhibitors.

Introduction: PDE2 is a dual-specific enzyme that hydrolyzes two intracellular substrates, cAMP and cGMP. PDE2 is mainly distributed in the brain, which indicates that PDE2 can serve as a potential target for central nervous system diseases without causing other peripheral side effects. Discovery of new mechanisms of PDE2 inhibitors is expected to bring new opportunities for the treatment of central nervous system diseases.

Area covered: This review aims to provide an overview of PDE2 inhibitors reported in patents from 2017 to present.

Expert opinion: In recent years, the development of PDE2 inhibitors and their application in the treatment of brain diseases have received much attention. The main reason is the high expression of PDE2 in the brain, which gives PDE2 a natural advantage as a research target for central nervous system diseases. This review summarizes the scaffolds of PDE2 inhibitors reported in various patents since 2017, as well as the scientific issues that need to be addressed in terms of subtype selectivity and metabolic stability, intending to provide insights for the discovery of highly active and selective PDE2 inhibitors in the future.

Introduction: Lactate dehydrogenase (LDH) is a key enzyme in glycolysis responsible for the conversion of pyruvate into lactate and vice versa. Lactate plays a crucial role in tumor progression and metastasis; therefore, reducing lactate production by inhibiting LDH is considered an optimal strategy to tackle cancer. Additionally, dysregulation of LDH activity is correlated with other pathologies, such as cardiovascular and neurodegenerative diseases as well as primary hyperoxaluria, fibrosis and cryptosporidiosis. Hence, LDH inhibitors could serve as potential therapeutics for treating these pathological conditions.

Areas covered: This review covers patents published since 2014 up to the present in the Espacenet database, concerning LDH inhibitors and their potential therapeutic applications.

Expert opinion: Over the past 10 years, different compounds have been identified as LDH inhibitors. Some of them are derived from the chemical optimization of already known LDH inhibitors (e.g. pyrazolyl derivatives, quinoline 3-sulfonamides), while others belong to newly identified chemical classes of LDH inhibitors. LDH inhibition has proven to be a promising therapeutic strategy not only for preventing human pathologies, but also for treating animal diseases. The published patents from both academia and the pharmaceutical industry highlight the persistent high interest of the scientific community in developing efficient LDH inhibitors.

Introduction: Aldose reductase (AKR1B1, EC: 1.1.1.21) is a recognized target for the treatment of long-term diabetic complications since its activation in hyperglycemia and role in the polyol pathway. In particular, the tissue-specificity of AKR1B1 expression makes the design of the traditional Aldose Reductase Inhibitors (ARIs) and the more recent Aldose Reductase Differential Inhibitors (ARDIs) exploitable strategies to treat pathologies resulting from diabetic conditions.

Areas covered: A brief overview of the roles and functions of AKR1B1 along with known ARIs and ARDIs was provided. Then, the design of the latest inhibitors in the scientific scenario was discussed, aiming at introducing the research achievement in the field of intellectual properties. Patents dealing with AKR1B1 and diabetes filed in the 2019-2023 period were collected and analyzed. Reaxys, Espacenet, SciFinderⁿ, and Google Patents were surveyed, using 'aldose reductase' and 'inhibitor' as the reference keywords. The search results were then filtered by PRISMA protocol, thus obtaining 16 records to review.

Expert opinion: Although fewer in number than in the early 2000s, patent applications are still being filed in the field of ARIs, with a large number of Chinese inventors reporting new synthetic ARIs in favor of the repositioning approach.

Background: It is more than two decades since IRAK4, a promising target for therapies against various medical conditions, was first reported, but no compounds targeting this enzyme are active on the market or under late-stage clinical development. So it is necessary to continue exploring new and/or improved chemotypes for IRAK4-targeting compounds, to which updated patent reviews are supposed to be of considerable contribution.

Areas covered: PCT patents claiming IRAK4-targeting compounds and published through 2019 to present were retrieved, screened and reviewed for the title compounds disclosed therein, where chemotype-specific strategies were adopted for the said reviewing process. Included patents featuring non-Protac compounds were described in terms of generic formulas and variable-indicated moieties of the title compounds, as well as selected title compounds and relevant prior documents. Included patents featuring Protac-based compounds were described in terms of general examples of IRAK-binding moieties and ligase-binding moieties, as well as the presence of conventional linker types. Insights were finally extracted from the patent review.

Expert opinion: The last five years has seen a steady increase in the number of PCT patents claiming IRAK4-targeting therapeutic compounds, with some of them being based on new chemotypes and/or discovered by new organizations as potential new players.

Introduction: The main enzymes that hydrolyzes nucleotides at the cell surface are nucleoside triphosphate diphosphohydrolases (NTPDases), ecto-nucleotide pyrophosphatases/phosphodiesterases (ENPPs), alkaline phosphatases (APs) and ecto-5'- nucleotidase (e5'NT, CD73) and by regulating the concentration of nucleotides at the cell surface, these enzymes have the potential to affect various conditions such as fibrosis, cancer metastasis, pruritus, inflammation, and autoimmune diseases. Thus, they represent a prospective therapeutic target.

Area covered: A number of molecules, including nucleoside/nucleotide and non-nucleoside analogues, and bicyclic compounds, have shown strong potential as ectonucleotidase inhibitors. This review covers the chemistry and clinical uses of ectonucleotidase inhibitors patented between 2017 and 2023.

Expert opinion: By binding to their specific P1 and P2 receptors at the cell surface, nucleosides and nucleotides regulate a number of pathophysiological events such as inflammation, fibrosis, cancer, and autoimmune diseases. Interestingly, these nucleotides can be hydrolyzed to nucleosides by several cell surface enzymes called ectonucleotidases. The development of small molecules that modulate ectonucleotidase activity is, therefore, of therapeutic value. This review provides valuable insights into recent advancements, including combination therapy and enhanced selectivity, which are poised to shape the future of ectonucleotidase inhibition through a comprehensive analysis of patents.

Introduction: CD38 and BCMA are proteins expressed at high levels in multiple myeloma cells, so they are targets for the development of mono- or multispecific antibodies.

Areas covered: Patent US20240132615 describes anti-CD3/BCMA/CD38 trispecific antibodies and a method of treating relapsed/refractory multiple myeloma pharmaceutically. In vitro and preclinical results show that anti-CD3/BCMA/CD38 trispecific antibodies have stronger binding affinity and killing potency compared to daratumumab, isatuximab, and teclistamab antibodies.

Expert opinion: The trispecific structure and a silenced Fc are pharmaceutical advantages of the anti-CD3/BCMA/CD38 antibody for the treatment of relapsed or refractory multiple myeloma.