ABSTRACT
A snapshot of noteworthy recent developments in the patent literature of relevance to pharmaceutical and medical research and development.
KEYWORDS: Acute infections, intellectual property, respiratory infections, pharmacokinetics/pharmacodynamics, mixed infections
1. WO/2024/114781
1.1. Title: tpk agonist and method for using same to treat neurodegenerative disease
1.1.1. Inventors: Zhang H, Meng L
1.1.1.1. Applicant:Shanghai Raising Pharmaceutical Co., Ltd., Shanghai (China)
Glucose metabolic disorder may be an early clinical feature of Alzheimer’s disease, mainly characterized by a significant decrease in the activity of the key enzymes (pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and ketolase) that rely on thiamine diphosphate (TDP) as coenzyme. Multi-center clinical studies prove that the TDP level drop of Alzheimer patients is a specific and universal phenomenon with good diagnostic value, thiamine metabolism abnormality being absent in patients with vascular dementia and frontotemporal dementia [1]. There is a genetic neurobehavioral condition named thiamine metabolism dysfunction syndrome 5 (THMD5; OMIM 614,458) that is caused by mutations in TPK1 (the gene coding thiamine pyrophosphate kinase which synthesizes TDP) which can be treated with thiamine and biotin [2], but no compounds that are unrelated to the substrate of this kinase and enhance its activity seem to have been reported in the literature. The inventors have synthesized 178 such molecules, determined the maximal enzymatic enhancement values (typically 120–200% of the baseline) for all of them, and EC50 values (typically in the low micromolar range) for about half of them. One of the best examples is 6-(4-(4-(benzo [d] thiazol-2-yl) piperazin-1-yl) butoxy) indolin-2-one, with an Emax of 235% and an EC50 of 1.14 µM,
Published: 6 June 2024
MeSH Keywords: Alzheimer disease/thiamin-diphosphate kinase, biomarkers
2. WO/2024/118378
2.1. Title:Long non-coding RNA LIPTER preserves lipid metabolism of the human heart
2.1.1. Inventors:Yang L
2.1.1.1. Applicant: The trustees of Indiana University, Bloomington (USA)
This document discloses that a lipid droplet transport system has been identified in human cardiomyocytes that functions via Lipid-droplets Transfer long non-coding RNA (LIPTER), thereby preserving lipid metabolism of the human heart. it is believed that LIPTER directly binds phosphatidic acid and phosphatidylinositol 4-phosphate on the lipid droplet surface membrane and non-muscle myosin IIB (Myh10) protein via different domains, which links the droplets to actin in the cytoskeleton to facilitate lipid transport. LIPTER transcription is primarily controlled by the NKX2-5 gene encoding a homeobox-containing transcription factor, which is specifically expressed in cardiac progenitor cells and cardiomyocytes, and functions in heart formation and development. To test if gain-of-LIPTER could ameliorate lipid metabolism abnormality associated cardiomyopathy in obesity and diabetes and prevent subsequent cardiac dysfunction, a transgenic mouse line was generated by knocking in LIPTER into the Rosa26 locus. After being kept on a high-fat diet for 7 months to induce lipid droplet accumulation, obesity, insulin resistance and cardiac abnormalities. LIPTER(Tg) mice showed no significant changes of heart weight/tibia length ratio compared to wildtype controls. However, LIPTER(Tg) hearts had significantly reduced lipid droplet, fatty acid and triacylglycerol concentrations, and their baseline fatty acid oxidation rate was significantly enhanced. Similar effects on cardiomyopathy were found with cardiomyocyte-specific LIPTER transgene therapy of leptin receptor deficient Lepr-db/db mice, which is a mouse genetic model of type 2 diabetes and obesity. - For the peer review companion paper see Han et al.
Published:6 June 2024
MeSH Keywords: Cardiomyopathies/Lipids/RNA, Long Noncoding
3. WO/2024/121113
3.1. Title:Adamts12 as a target molecule for the treatment of chronic renal insufficiency and renal fibrosis
3.1.1. Inventors:Kramann R, Hoefft K, Koch LL
3.1.1.1. Applicant:Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen (Germany)
A microarray analysis of total mouse kidney transcriptome after induction of fibrosis by unilateral urether obstruction, with fibroblasts expressing the transcription factor Gli1, allowed the researchers to identify Adamts12, one of the less well explored disintegrins and metalloproteinases, as one of the most strongly upregulated proteins, and as a new mediator of renal fibrosis. Knocking out ADAMTS12 in mice prevents renal fibrosis and progression not only of chronic kidney disease but also of cardiac fibrosis. To determine whether Adamts12 could be essential for fibroblasts, ADAMTS12 knockouts were induced in immortalized human renal PDGFRb-positive fibroblasts using CRISPR-Cas9, and stimulated with TGFbeta to investigate the expansion and myofibroblast differentiation. As expected, expression of collagen-1 was reduced, as was the migration of fibroblasts. As the upregulation of Adamst12 is restricted to fibroblasts and myofibroblasts (and to a much smaller extent, pericytes), inhibiting it might be associated with limited side effects. - For the peer review companion paper see Hoeft et al.[3].
Published:13 June 2024
MeSH Keywords: ADAMTS12 protein, human//Fibrosis/Renal Insufficiency, Chronic
4. WO/2024/126630
4.1. Title:Purine nucleoside phosphorylase inhibitors for the treatment of metabolic syndrome and associated conditions
4.1.1. Inventors: Mehrling T, Bantia S
4.1.1.1. Applicants: Metashape Pharma AG, Riehen (Switzerland)
Purine nucleoside phosphorylase (PNP) is the key enzyme involved in purine metabolic pathways; it catalyzes the conversion of (2’-deoxy)nucleosides to the corresponding purine bases and (2-deoxy)ribose-1-phosphate, for example inosine into hypoxanthine plus ribose phosphate [4]. Several small-molecule PNP inhibitors have been developed so far to disrupt the cellular purine pool in conditions requiring it. However, only peldesine, forodesine and ulodesine have entered clinical trials and exhibited some potential for the treatment of T-cell leukemia and gout [5]. This patent application extends the range to the treatment and/or prevention of metabolic syndrome and diseases and conditions that are induced by it; and to the treatment or prevention of diseases and conditions associated with decline of the metabolite, NAD+. The disclosure further identifies and characterizes the preferred salt forms of ulodesine and pharmaceutical compositions. The rationale is that treatment of healthy subjects with PNP inhibitors leads to increased levels of inosine [6], which stimulates energy expenditure in brown adipocytes via the cAMP/PKA signaling pathway [7]. C57/BL6J mice were fed obesogenic diet D12492 from age 6 weeks. Nineteen-week-old mice were either treated with vehicle or ulodesine hemiglutarate (the preferred PNP inhibitor; see the inventors’ WO/2023/001893).at 2 mg/kg for 3 days a week over a 28 day period. The ulodesine treated group showed decreases in blood glucose, plasma cholesterol, AST and ALT and insulin levels compared to the control group. The ulodesine treated group demonstrated an increase in expression of the thermogenic marker, UCP-1 in brown adipose tissue and a decrease in lipogenesis markers (SCD-1 and FAS) in white fat tissue compared to the vehicle treated group. Both inosine and NAD+ were significantly elevated in plasma and whole blood respectively
Published: 20 June 2024
MeSH Keywords: Adipose Tissue/Obesity/Purine-Nucleoside Phosphorylase/ulodesine
5. WO/2024/126793
5.1. Title: Dpp3 inhibitor for improvement of pulmonary function in critically ill patients
5.1.1. Inventors: Bourgeois K, Bergmann a
5.1.1.1. Applicant: 4Thee4 Pharmaceuticals GmbH, Henningsdorf (Germany)
Dpp3 is one of seven dipeptiyl exo-peptidases, with an activity optimum at pH 8–9 and a broad substrate specificity for oligopeptides from three or four to ten amino acids of various compositions. It hydrolyzes bioactive dipeptides (angiotensins; enkephalins, endorphins) from the N-terminus. As with the related Dpp4, its preferred substrate is angiotensin-II. Circulating Dpp3 levels are increased in septic, cardiogenic and vasodilatory shock patients [8,9]. The examples in this document show that procizumab, a humanized IgG1 monoclonal antibody, can modulate Dpp3 activity in vivo. Procizumab injection in pigs with septic shock resulted in a marked improvement of pulmonary function as given by PaO2/FiO2 ratio (a clinical indicator of hypoxemia) and the chest-lung static compliance (a measure of the ability of the lungs to expand during inspiration) compared to placebo. Furthermore, it was demonstrated that circulating Dpp3 was significantly elevated in all intensive care unit patient patients under ventilation, especially mechanical ventilation. Patients with Dpp3 levels below 40 ng/mL had a 28-day survival rate of 74.2%, while patients with cDpp3 above 40.0 ng/mL had a mortality rate of only 55.5% (HR 2.1, 95-% CI 1.5–2.9, p < 0.0001). Therefore, it is plausible that procizumab can improve pulmonary function in patients with reduced lung function who are ventilated, irrespective of the indication.
Published: 20 June 2024
MeSH Keywords: Critical Care/DPP3 protein, human/Procizumab/Respiration, Artificial
6. WO/2024/133215
6.1. Title: Uroporphyrin I as therapeutic compound against prion diseases
6.1.1. Inventors: Castilla Castrillon J, Eraña Lasagabaster H, Morreno Charco J, Garcìa Martinez S, Bernardo-Seisdedos G
6.1.1.1. Applicant: Asociaciòn Centro de Investigaciòn Cooperativa en Biociencias-Cic Biogune, Derio (Spain) and Atlas Molecular Pharma S.L., Derio (Spain)
Creutzfeldt – Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia are neurodegenerative diseases caused by a prion protein (PrP), that is normally produced in the nervous system, but aggregates in an abnormal refolded form [10]. Given the particular propagation mechanism of prions, the presence of the natively folded or cellular PrP isoform, able to adopt a prion conformation, is essential as a conversion substrate for prion multiplication and spreading, and thus for the development of the neurodegenerative pathology [11]. The anti-prion activity of cyclic tetrapyrroles, such as porphyrins, is known [12]. Using brain homogenates from mice and the murine prion strain RML as seed, the inventors have established that one physiologically occurring member of this class, uroporphyrin I (the heme biosynthesis intermediate which accumulates in congenital erythropoietic porphyria) is able to inhibit prion propagation in vitro about 125 times better than TMPyP-Fe3+, the most effective anti-TSE porphyrin described so far. Uroporphyrin I showed similar inhibitory capacity for strains 22 L and 301C, suggesting a strain-independent mechanism of action. In the case of recombinant human PrP with the M129 variant, the inhibitory effect was reduced with respect to the V129 variant, reaching a 5-log reduction at 50 µM, 4 logs at 20 and 2 logs at 10 µM. These results suggest that uroporphyrin I might exert a differential effect possibly due to distinct binding affinities to M129 or V129 variants, suggesting a mechanism of action dependent on uroporphyrin-PrPc binding.
Published:27 June 2024
MeSH Keywords: Prion Proteins/uroporphyrin I
7. WO/2024/137607
7.1. Title:Thiadiazole derivatives as inhibitors of cyclic GMP-AMP synthase and uses thereof
7.1.1. Inventors: Beveridge R, Burch J, Ciblat S, Cyr P
7.1.1.1. Applicant: Ventus Therapeutics U.S., Inc., Waltham (USA)
cGAS is the synthase for the second messenger cyclic GMP – AMP (cGAMP). With the corresponding receptor stimulator of interferon genes (STING), cGAS and cGAMP constitute a signaling axis that responds to cytosolic DNA and is important for antimicrobial defense but can also induce autoimmunity [13]. Besides sensing free DNA cGAS is essential in cellular senescence, and recognition of ruptured micronuclei in the surveillance of potential cancer cells [14]. Small molecule inhibitors of cGAS have been described [15,16]. This document presents 231 novel thiadiazole cGAS inhibitors with IC50 values that in some cases reach below 5 nM when tested for their inhibition of human cGAS activity using direct measurement of cGAMP production by LC/MS – a massive improvement over e.g., PF-06928215 (IC50 value of 4.9 μM).
Published: 27 June 2024
MeSH Keywords: Cell-Free Nucleic Acids/cGAS protein, human/cyclic guanosine monophosphate-adenosine monophosphate
8. WO/2024/144164
8.1. Title: Pharmaceutical composition containing graphene quantum dots as active ingredient for prevention or treatment of chemotherapy-induced nephrotoxicity
8.1.1. Inventors: Hong BH, Yang SH, Park JB
8.1.1.1. Applicants: Seoul National University R&DB Foundation, Seoul (Korea); Graphene Square Chemical Inc., Pohang-si (Korea)
Layers of graphene sheets, which are planar honeycomb-like polycyclic carbon nanostructures, can assemble into quantum dots with sizes ranging from a few nanometers to 100 nm. Due to the large surface-to-volume ratio, low apparent cytotoxicity, easy functionalization at the edges, and their nature of being entirely composed of a carbon allotrope, graphene quantum dots (GQDs) have become extremely popular in the emerging field of nanobiotechnology. Applications have been reported in drug delivery, tissue engineering, photodynamic therapy, antimicrobial activity, bioimaging, and biosensing [17]. GQDs functionalized with phenol-like groups that have both high reactive oxygen scavenging efficacy and renal specificity have shown promising results in animal models of acute kidney injury [18]. No derivatization seems to have taken place for the present invention which claims GQDs for treating and preventing kidney injury caused by cancer chemotherapeutics: GQDs were produced by heating carbon fibers with sulfuric and nitric acid, a standard procedure. In a murine model of adriamycin-induced kidney toxicity, these had a strong positive effect on renal function markers (blood urea nitrogen, creatinine, and total urinary protein/creatinine ratio). Additional biomarker studies, gene set enrichment analysis, histopathology, and permeability assays confirmed improvements in glomerular damage, podocyte function, inflammation, and fibrosis.
Published: 4 July 2024
MeSH Keywords: Carbon/Quantum Dots/Reactive Oxygen Species
9. WO/2024/148272
9.1. Title: Aza bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors
9.1.1. Inventor: Hawley R
9.1.1.1. Applicant: Riboscience LLC, Palo Alto (USA)
Enpp1 is an ubiquitous type II transmembrane enzyme that hydrolyzes ATP and other nucleoside triphosphates and releases the corresponding nucleoside monophosphates as well as pyrophosphate [19]. It can attenuate STING-mediated inflammation by removing extracellular cGAMP (see discussion of WO/2024/137607, above) [20]. While severe genetic Enpp1 deficiency causes devastating rare disease phenotypes [21], pathologically elevated levels of Enpp1 are associated with cancer, calcific aortic valve disease and calcium pyrophosphate dihydrate disease, an inflammatory disease resulting from calcium pyrophosphate dihydrate crystal deposits in the joint and surrounding tissues. Small molecule inhibitors have been described, e.g., phtalazinones. The chemical space for non-nucleotide based molecules with this activity is expanded to novel compounds with Ki values from 1–5 nM, e.g., (4-(((6-methoxyquinoxalin-2-yl)oxy)methyl)phenyl)boronic acid.
Published: 11 July 2024
MeSH Keywords: cyclic guanosine monophosphate-adenosine monophosphate/ectonucleotide pyrophosphatase phosphodiesterase 1
10. WO/2024/149820
10.1. Title: Nmu receptor 2 agonists
10.1.1. Inventors:Wagner H, Baljuls A, Brennauer A, Fox TS, Volker M, Peters S, et al
10.1.1.1. Applicant:Boehringer Ingelheim International GmbH, Ingelheim a. Rhein (Germany)
The neuromedin U receptor 2 (Nmur2) is one of two major neuromedin receptors, primarily expressed in the central nervous system, where it has a central role in appetite regulation and energy homeostasis. PEGylated neuromedin peptide analogs have been investigated as treatments for obesity, diabetes, and metabolic disorders; however, they are prone to accumulation and vacuole formation in organs. The peptides of the invention are analogs of neuromedin U-8 (NMU-8; a truncated version of neuromedin U) where at position 3 the leucine residue present in NMU-8 is changed to a N-methyl-leucine; at position 4 the phenylalanine is changed to a norleucine residue; at position 8 the asparagine is changed to a glycine residue. Moreover, at position 5 and 6 the arginine and the proline present in NMU-8 respectively can be changed. The NMU-8 analogs also carry 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl, or 19-carboxy-nonadecanoyl lipophilic substituents that are believed to bind to albumin and other plasma components, shielding the compounds from renal filtration as well as enzymatic degradation and thus possibly enhancing the half-life of the peptide analogs in vivo. No data are presented in support of this, but Ki values for binding of 23 NMU-9 analogs to Nmur1 and Nmur2 expressed in CHO-K1 cells are made available, showing extremely high selectivity for Nmur2.
Published: 18 July 2024
MeSH Keywords: Metabolic Syndrome/neuromedin U 8/neuromedin U receptor
11. WO/2024/151996
11.1. Title:Intelectin-1 (Itln-1) inhibitors for use in treating mucus obstruction in severe asthma
11.1.1. Inventors: Seibold MA, Everman JL
11.1.1.1. Applicant: National Jewish Health, Denver (USA)
Overproduction of mucus occurs in all inflammatory diseases of the airways, but while several efficacious drugs are available to alleviate bronchoconstriction in asthma, clinical development of mucolytic agents has been slow. To date, even the structure of pathologic airway mucus (which in asthma shifts from the normal predominance of MUC5B mucin toward higher expression of mucostatic MUC5AC) has been poorly characterized [22]. Mucus plugs identify a persistent asthma phenotype [23]. By using mucus fraction proteomics, scRNA-seq analysis of bronchial brushings, and CRISPR gene editing of human mucociliary airway epithelia, the inventors demonstrate a role of the Itln-1 protein in IL-13-induced mucostasis, and the ability of Itln-1 to bind airway mucins via non-lectin based electrostatic interactions; this results in mucin cross-linking and altered visco-elastic properties of mucus. Primary nasal airway epithelial brushes were obtained from children recruited for the Genes-environments and Admixture in Latino Americans II (GALA II) childhood asthma study for genotyping and transcriptomic analysis. The genetic and inflammatory regulators of Itln1 expression were defined and the inventors show how functional genetic variation in the ITLN1 gene influences susceptibility to airway mucus plugging; the eQTL variant rs4656959 is on top of the protective variant list. No specific Itln1 inhibitors are described or claimed.
Published: 18 July 2024
MeSH Keywords: Asthma/ITLN1 protein, human/MUC5AC protein, human/MUC5B protein, human/
12. WO/2024/153249
12.1. Title:Compound as Pkmyt1 inhibitor
12.1.1. Inventors: Zhang H, Cai C, Zhu S
12.1.1.1. Applicants: Hangzhou Innogate Pharma Co. Ltd, Hangzhou (China); Innorace Biopharma Co., Ltd., Hangzhou (China)
The three-member Wee1 kinase family, which consists of Wee1, Wee1B,and Pkmyt1 (a membrane-associated kinase that inhibits Cdc2 by phosphorylating it on residue Thr14) [24] is among the most promising targets for inhibition of the DNA damage identification and repair mechanism in both normal and cancer cells. Wee1 and Pkmty1 act as tumor suppressors in nonmalignant eukaryotic somatic cells, but as pseudo-oncogenes in cancer cells [25,26]. While Wee1 is located in the nucleus, Pkmty1 is associated with the endoplasmic reticulum and Golgi apparatus, and regulates Golgi membrane reassembly following mitosis [27]; this makes it relatively easy to access by small molecule inhibitors. RP6306 is an orally bioavailable clinical-stage candidate [28]. The present inventors have improved on it by varying its structure only slightly, keeping the dimethylphenol substituent and adding a CF2-substituted pyridine substituent, to arrive at compounds such as the one identified as 4B. Its IC50 is below 5 nM and its pharmacokinetics were investigated in mice; plasma half-life after 1 mg/kg administered intravenously was 2.02 hrs and 2.71 hrs after 5 mg/kg. given intragastrically.
Published: 25 July 2024
MeSH Keywords: DNA Repair Enzymes/Neoplasms/PKMYT1 protein, human
Funding Statement
This work was not funded.
Declaration of Interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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