Expert Opinion on Therapeutic Patents最新文献

Introduction: Phosphodiesterase 9 (PDE9) has been demonstrated as a potential target for neurological disorders and cardiovascular diseases, such as Alzheimer's disease and heart failure. For the last few years, a series of PDE9 inhibitors with structural diversities have been developed and patented by researchers and pharmaceutical companies, providing insights into first-in-class therapies of PDE9 drug candidates.

Area covered: This review provides an overview of PDE9 inhibitors in patents from 2018 to the present.

Expert opinion: Only a few of the current PDE9 inhibitors are highly selective over other PDEs, which limits their application in pharmacological and clinical research. The design and development of highly selective PDE9 inhibitors remain the top priority in future research. The advantages of targeting PDE9 rather than other PDEs in treating neurodegenerative diseases need to be explained thoroughly. Besides, application of PDE9 inhibitor-based combination therapies sheds light on treating diabetes and refractory heart diseases. Finally, PDE9 inhibitors should be further explored in clinical indications beyond neurological disorders and cardiovascular diseases.

Introduction: Boswellic acids (BAs) are a group of pentacyclic triterpenoids of the ursane and oleanane type. They have shown very interesting biological properties that have led to the development of a number of synthesis protocols. Both natural BAs and their synthetic derivatives may be useful in the treatment of a variety of cancers, viral infections and inflammatory diseases.

Areas covered: This review covers patents relating to the therapeutic activities of natural BAs and their synthetic derivatives. The latest patented studies of boswellic acids (are summarized by using the keywords 'boswellic acid,' in SciFinder, PubMed, and Google Patents and databases in the year from 2016 to 2023.

Expert opinion: Boswellic acids have shown potent antiviral, anticancer and anti-inflammatory potential. Few BAs analogues have been prepared by modification at the C24-CO₂H functional groups. In particular, the C-24 amide and amino analogues have shown enhanced anticancer effects compared to the parent AKBA. In addition, BAs have the ability to form conjugates with other antiviral, anti-inflammatory and anticancer drugs that synergistically enhance their biological efficacy. In addition, this conjugation strategy will increase the solubility and bioavailability of BAs, which is one of the most important issues in the development of BAs.

Introduction: The P2Y₁₄ receptor (P2Y₁₄R), a member of the G protein-coupled receptor family, is activated by extracellular nucleotides. Due to its involvement in inflammatory, immunological and other associated processes, P2Y₁₄R has emerged as a promising therapeutic target. Despite lacking a determined three-dimensional crystal structure, the homology modeling technique based on closely related P2Y receptors' crystallography has been extensively utilized for developing active compounds targeting P2Y₁₄R. Recent discoveries have unveiled numerous highly effective and subtype-specific P2Y₁₄R inhibitors. This study presents an overview of the latest advancements in P2Y₁₄R inhibitors.

Areas covered: This review presents an overview of the advancements in P2Y₁₄R inhibitor research over the past five years, encompassing new patents, journal articles, and highlighting the therapeutic prospects inherent in these compounds.

Expert opinion: The recent revelation of the vast potential of P2Y₁₄R inhibitors has led to the development of novel compounds that exhibit promising capabilities for the treatment of sterile inflammation of the kidney, potentially diabetes, and asthma. Despite being a relatively nascent class of compounds, certain members have already exhibited their capacity to surmount specific challenges posed by conventional P2Y₁₄R inhibitors. Targeting P2Y₁₄R through small molecules may present a promising therapeutic strategy for effectively managing diverse inflammatory diseases.

Introduction: Cannabinoid receptor type 2 (CB₂R), predominantly expressed in immune tissues, is believed to play a crucial role within the body's protective mechanisms. Its modulation holds immense therapeutic promise for addressing a wide spectrum of dysbiotic conditions, including cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, and autoimmune diseases, as well as lung disorders, cancer, and pain management.

Areas covered: This review is an account of patents from 2016 up to 2023 which describes novel CB₂R ligands, therapeutic applications, synthesis, as well as formulations of CB₂R modulators.

Expert opinion: The patents cover a vast, structurally diverse chemical space. The focus of CB₂R ligand development has shifted from unselective dual-cannabinoid receptor type 1 (CB₁R) and 2 agonists toward agonists with high selectivity over CB₁R, particularly for indications associated with inflammation and tissue injury. Currently, there are at least eight CB₂R agonists and one antagonist in active clinical development. A better understanding of the endocannabinoid system (ECS) and in particular of CB₂R pharmacology is required to unlock the receptor's full therapeutic potential.

Introduction: KRAS is a critical oncogenic protein intricately involved in tumor progression, and the difficulty in targeting KRAS has led it to be classified as an 'undruggable target.' Among the various KRAS mutations, KRAS^G12D is highly prevalent and represents a promising therapeutic target, yet there are currently no approved inhibitors for it.

Area covered: This review summarizes numerous patents and literature featuring inhibitors or degraders of KRAS^G12D through searching relevant information in PubMed, SciFinder and Web of Science databases from 2021 to February 2024, providing an overview of the research progress on inhibiting KRAS^G12D in terms of design strategies, chemical structures, biological activities, and clinical advancements.

Expert opinion: Since the approval of AMG510 (Sotorasib), there has been an increasing focus on the inhibition of KRAS^G12D, leading to numerous reports of related inhibitors and degraders. Among them, MRTX1133, as the first KRAS^G12D inhibitor to enter clinical trials, has demonstrated excellent tumor suppression in various KRAS^G12D-bearing human tumor xenograft models. It is important to note, however, that understanding the mechanisms of acquired resistance caused by KRAS inhibition and developing additional combination therapies is crucial. Moreover, seeking covalent inhibition of KRAS^G12D also holds significant potential.

Introduction: Focal adhesion kinase (FAK) is a cytoplasmic non-receptor tyrosine kinase over-expressed in various malignancies which is related to various cellular functions such as adhesion, metastasis and proliferation.

Areas covered: There is growing evidence that FAK is a promising therapeutic target for designing inhibitors by regulating the downstream pathways of FAK. Some potential FAK inhibitors have entered clinical phase research.

Expert opinion: FAK could be an effective target in medicinal chemistry research and there were a variety of FAKIs have been patented recently. Here, we updated an overview of design, synthesis and structure-activity relationship of chemotherapeutic FAK inhibitors (FAKIs) from 2017 until now based on our previous work. We hope our efforts can broaden the understanding of FAKIs and provide new ideas and insights for future cancer treatment from medicinal chemistry point of view.

Introduction: Hypoxia-inducible factor (HIF) is a central regulatory factor in detecting and adapting to cellular oxygen stress. Dysregulation of HIF is associated with various human diseases. Seven HIF modulators, including six prolyl hydroxylase (PHD) inhibitors and one HIF-2α inhibitor, have already been approved for the treatment of renal anemia and cancer, respectively.

Areas covered: This review summarizes HIF modulators patented in the 2021-2023 period. This review provides an overview of HIF downregulators, including HIF-1α inhibitors, HIF-2α inhibitors, and HIF-2α degraders, as well as HIF upregulators, including PHD, FIH, and VHL inhibitors, and HIF-2α and HIF-3α agonists.

Expert opinion: Efforts should be made to address the adverse clinical effects associated with approved HIF-modulating drugs, including PHD inhibitors and HIF-2α inhibitors. Identification of the specific buried cavity in the HIF-2α and an opened pocket in HIF-3α offer an avenue for designing novel modulators for HIF-2α or HIF-3α. Given the similarities observed in the binding cavities of HIF-2α and HIF-3α, it should be considered whether the approved HIF-2α inhibitors also inhibit HIF-3α. A comprehensive understanding of the HIF signaling pathway biology would lead to the development of novel small-molecule HIF modulators as innovative therapeutic approaches for a wide range of human diseases.

Introduction: PD-L1, via its interactions with PD-1, constitutes a key immune checkpoint that allows cancer cells to escape immune surveillance. Targeting PD-1/PD-L1 with monoclonal antibodies (mAbs) led to spectacular success in clinical oncology. However, the inherent limitations of mAbs and increasing findings about immune-related adverse events (iRAEs) prompted intense research in the field of small-molecule inhibitors of PD-L1.

Areas covered: This review covers inhibitors of PD-L1 reported in patents published in the online databases of the World Intellectual Property Organization and European Patent Office in the 2022-2023 period. This review provides a landscape of available inhibitors, including their chemical structures, activity, and stage of development.

Expert opinion: Small-molecule inhibitors impairing PD-L1/PD-1 interaction represent an attractive alternative to mAbs. In recent years, the field of small-molecule and macrocyclic inhibitors targeting PD-L1 has grown rapidly. The majority (if not all) of small-molecule inhibitors developed recently, similarly to their predecessors, act through a dimerization mechanism of PD-L1, followed by its internalization into the cytosol. In contrast, macrocyclic peptides act purely through a competition mechanism known as protein-protein interaction inhibitors. The ongoing clinical trials should ultimately reveal which strategy has real clinical potential and may complement or even replace mAbs-based therapies.

Introduction: Protein kinases (PKs) play key roles in cellular signaling and regulation cascades and therefore are listed among the most investigated enzymes with the intent to develop drugs that are able to modulate their catalytic features. Specifically, PKs are involved in chronic diseases of large impact in the society such as cancers and neurodegeneration. Since the approval of Fasudil for the management of cerebral vasospasm, frantic efforts are currently ongoing for the development of selective PK-modulating agents.

Areas covered: A selection of the most relevant patents in the European Patent Office for biomedical innovation and/or industrial development covering the years 2020-2023 on PK modulators either of the antibody and small-molecule type is reported. In addition to the examined patents, we also reported the contributions claiming the use of antibody-targeted PKs for lab bench identification kits.

Expert opinion: The field of PK modulators for biomedical purposes is particularly crowded with contributions, making it rich in valuable information for the development of potential drugs. An emerging frontier is represented by PK activators that aims to complement the use of PK inhibitors with the final intent of finely adjusting any PK-related disruption responsible for triggering any disease.