Expert Opinion on Therapeutic Patents最新文献

Introduction: SOS1 is a crucial guanine nucleotide exchange factor for KRAS. It facilitates the transition of KRAS from inactive GDP-bound state to active GTP-bound state. The activation of KRAS triggers downstream signaling pathways, promoting tumor initiation and progression. Inhibiting SOS1 to prevent KRAS activation is an effective strategy for treating tumors driven by KRAS.

Areas covered: This review identified patents claiming to be SOS1 inhibitors or SOS1-KRAS interaction modulators published between January 2022 and June 2024 using Cortellis Drug Discovery Intelligence. A total of 15 patent applications from 5 different applicants were assessed.

Expert opinions: In KRAS-driven tumors, inhibiting SOS1 significantly affect cell proliferation and migration by modulating the RAS/MAPK and PI3K/AKT/mTOR signaling pathways. Since 2022, numerous patents for SOS1 inhibitors have been published. The majority of SOS1 inhibitors are currently in the preclinical phase of development, with only a few progressing to clinical trials. However, these inhibitors face significant challenges in clinical studies, including limited efficacy of monotherapies, safety concerns, and the necessity to enhance PK properties. Despite their excellent in vitro performance, SOS1 inhibitors must address issues related to safety, pharmacokinetics, and pharmacodynamics in clinical applications.

Introduction: Coumarins constitute a family of heterocyclic compounds that have been extensively studied as possible drugs in the pharmaceutical research to support human health.

Areas covered in this review: A survey of patent publications from 2017 to mid-2024, taken from Google Scholar, Web of Science, Scopus, or PubMed analyzes coumarins and their derivatives. It covers synthetic methods, hybridization techniques, and assessments of their biological effects in laboratory and biological studies, such as cytotoxic, antitumor, anticancer, cardiovascular, anti-atheromatic, antidiabetic, anti-asthmatic and antioxidant properties. Additionally, it presents and discusses several pharmaceutical applications for treatment and compositions involving these compounds. Structural activity relationships and mechanism of action are presented and discussed.

Expert opinion: The authors suggest that (i) numerous areas of biology-pharmacology need to be considered: selectivity, in vivo studies, toxicity, bioavailability and drug-likeness, the mechanism of action in animals and humans, evaluation of more efficient and selective biological tests; (ii) synthetic technique outbalance in the discovery and production of coumarins with greater selectivity. Their clinical evaluation will be critical to assess therapeutic utility. The coumarins, for which extended biological investigations confirmed their mechanism of action, can serve as lead or hit structures for the design of new libraries with more potent molecules.

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: The activity of the major tumor suppressor protein p53 is disrupted in nearly all human cancer types, either by mutations in TP53 gene or by overexpression of its negative regulator, Mouse Double Minute 2 (MDM2). The release of p53 from MDM2 and its homolog MDM4 with inhibitors based on different chemistries opened up a prospect for a broad, non-genotoxic anticancer therapy.

Areas covered: This article reviews the patents and patent applications between years 2019 and 2023 in the field of MDM2-p53 interaction inhibitors. The newly reported molecules searched in Espacenet, Google Patents, and PubMed were grouped into five general categories: compounds having single-ring, multi-ring, or spiro-oxindole scaffolds, peptide derivatives, and proteolysis-targeting chimeras (PROTACs). The article also presents the progress of MDM2 antagonists of various structures in recruiting or completed cancer clinical trials.

Expert opinion: Despite 20 years of intensive studies after the discovery of the first-in-class small-molecule inhibitor, Nutlin-3, no drugs targeting MDM2-p53 interaction have reached the market. Nevertheless, more than 10 compounds are still being evaluated in clinics, both as standalone drugs and in combinations with other targeted therapies or standard chemotherapy agents, including two inhibitors in phase 3 studies and two compounds granted orphan-drug/fast-track designation by the FDA.

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: c-Jun N-terminal kinase (JNK) regulates various biological processes through the phosphorylation cascade and is closely associated with numerous diseases, including inflammation, cardiovascular diseases, and neurological disorders. Therefore, JNKs have emerged as potential targets for disease treatment.

Areas covered: This review compiles the patents and literatures concerning JNK inhibitors through retrieving relevant information from the SciFinder, Google Patents databases, and PubMed from 2015 to the present. It summarizes the structure-activity relationship (SAR) and biological activity profiles of JNK inhibitors, offering valuable perspectives on their potential therapeutic applications.

Expert opinion: The JNK kinase serves as a novel target for the treatment of neurodegenerative disorders, pulmonary fibrosis, and other illnesses. A variety of small-molecule inhibitors targeting JNKs have demonstrated promising therapeutic potential in preclinical studies, which act upon JNK kinases via distinct mechanisms, encompassing traditional ATP competitive inhibition, covalent inhibition, and bidentate inhibition. Among them, several JNK inhibitors from PregLem SA, Celegene SA, and Xigen SA have accomplished the early stage of clinical trials, and their results will guide the development and indications of future JNK inhibitors.