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Journal of Cellular and Molecular... Jan 2021Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and... (Clinical Trial)
Clinical Trial
Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and steroids, many patients can recover from severe CRS. However, some patients are refractory to steroids and develop life-threatening consequences. Ruxolitinib is an oral JAKs inhibitor and promising drug in inflammatory diseases. In this pilot study, we evaluate the efficacy of Ruxolitinib in CRS. Of 14 r/r B-ALL children who received CD19 or CD22 CAR T cell therapies, 4 patients developed severe (≥grade 3) CRS with symptoms that were not alleviated with high-dose steroids and thus received ruxolitinib. Rapid resolution of CRS symptoms was observed in 4 patients after ruxolitinib treatment. Serum cytokines significantly decreased after ruxolitinib intervention. All patients achieved complete remission on day 30 after infusion, and we could still detect CAR T expansion in vivo despite usage of ruxolitinib. There were no obvious adverse events related to ruxolitinib. In vitro assays revealed that ruxolitinib could dampen CAR T expansion and cytotoxicity, suggesting that the timing and dosage of ruxolitinib should be carefully considered to avoid dampening anti-leukaemia response. Our results suggest that ruxolitinib is active and well tolerated in steroid-refractory and even life-threatening CRS.
Topics: Adolescent; Cell Proliferation; Child; Child, Preschool; Cytokine Release Syndrome; Cytokines; Dexamethasone; Female; Humans; Immunotherapy, Adoptive; Male; Nitriles; Pilot Projects; Pyrazoles; Pyrimidines; Steroids; Treatment Outcome
PubMed: 33314568
DOI: 10.1111/jcmm.16176 -
Scientific Reports Mar 2020Bipyrazone, 1,3-dimethyl-4-(2-(methylsulfonyl)-4-(trifluoromethyl) benzoyl)-1H-pyrazol-5-yl 1,3-dimethyl-1H-pyrazole- 4-carboxylate, is a 4-hydroxyphenylpyaunate...
Bipyrazone, 1,3-dimethyl-4-(2-(methylsulfonyl)-4-(trifluoromethyl) benzoyl)-1H-pyrazol-5-yl 1,3-dimethyl-1H-pyrazole- 4-carboxylate, is a 4-hydroxyphenylpyaunate dioxygenase (HPPD)-inhibiting herbicide. Greenhouse and field experiments were conducted to explore the potential of post-emergence (POST) application of bipyrazone in wheat fields in China. In the greenhouse study, bipyrazone at 10 and 20 g active ingredient (a.i.) ha effectively controlled Descurainia sophia L., Capsella bursa-pastoris (L.) Medic., Lithospermum arvense L. and Myosoton aquaticum L. Whereas, all tested 16 wheat cultivars showed high degree of tolerance to bipyrazone at 375 and 750 g a.i. ha. In a dose-response experiment carried on the Shannong 6 wheat cultivar and five weed biotypes, bipyrazone was safe to the wheat cultivar, and C. bursa-pastoris, M. aquaticum and D. sophia were sensitive to this herbicide. The selectivity index (SI) between the Shannong 6 and weeds ranged from 34 to 39. The field experiments confirmed that a mixture of bipyrazone and fluroxypyr-mepthyl is practical for controlling broadleaf weeds, and bipyrazone applied alone at 30 to 40 g a.i. ha can also provide satisfactory control of sensitive broadleaf weeds. These findings suggest that bipyrazone POST application has good potential for broadleaf weed management in wheat fields.
Topics: 4-Hydroxyphenylpyruvate Dioxygenase; Crops, Agricultural; Greenhouse Effect; Herbicide Resistance; Herbicides; Molecular Structure; Plant Proteins; Plant Weeds; Pyrazoles; Triticum
PubMed: 32218463
DOI: 10.1038/s41598-020-62116-6 -
Molecules (Basel, Switzerland) Jan 2023In our initial publication on the in vitro testing of more than 200 compounds, we demonstrated that small molecules can inhibit phagocytosis. We therefore theorized that...
In our initial publication on the in vitro testing of more than 200 compounds, we demonstrated that small molecules can inhibit phagocytosis. We therefore theorized that a small molecule drug discovery-based approach to the treatment of immune cytopenias (ITP, AIHA, HTR, DHTR) is feasible. Those earlier studies showed that small molecules with anti-phagocytic groups, such as the pyrazole core, are good models for producing efficacious phagocytosis inhibitors with low toxicity. We recently screened a chemical library of 80 compounds containing pyrazole/isoxazole/pyrrole core structures and found four hit molecules for further follow-up, all having the pyrazole core structure. Subsequent evaluation via MTT viability, LDH release, and apoptosis, led to the selection of two lead compounds with negligible toxicity and high efficacy. In an in vitro assay for inhibition of phagocytosis, their IC values were 2-4 µM. The rational development of these discoveries from hit to lead molecule stage, viz. independent synthesis/scale up of hit molecules, and in vivo activities in mouse models of autoimmune disease, will result in the selection of a lead compound(s) for further pre-clinical evaluation.
Topics: Mice; Animals; Phagocytosis; Drug Discovery; Pyrazoles; Structure-Activity Relationship
PubMed: 36677815
DOI: 10.3390/molecules28020757 -
Journal of the American College of... Mar 2020
Topics: Pyrazoles; Pyridones
PubMed: 32164889
DOI: 10.1016/j.jacc.2019.12.061 -
Molecules (Basel, Switzerland) Dec 2019Pyrazoles are known as versatile scaffolds in organic synthesis and medicinal chemistry, often used as starting materials for the preparation of more complex... (Review)
Review
Pyrazoles are known as versatile scaffolds in organic synthesis and medicinal chemistry, often used as starting materials for the preparation of more complex heterocyclic systems with relevance in the pharmaceutical field. Pyrazoles are also interesting compounds from a structural viewpoint, mainly because they exhibit tautomerism. This phenomenon may influence their reactivity, with possible impact on the synthetic strategies where pyrazoles take part, as well as on the biological activities of targets bearing a pyrazole moiety, since a change in structure translates into changes in properties. Investigations of the structure of pyrazoles that unravel the tautomeric and conformational preferences are therefore of upmost relevance. 3(5)-Aminopyrazoles are largely explored as precursors in the synthesis of condensed heterocyclic systems, namely pyrazolo[1,5-a]pyrimidines. However, the information available in the literature concerning the structure and chemistry of 3(5)-aminopyrazoles is scarce and disperse. We provide a revision of data on the present subject, based on investigations using theoretical and experimental methods, together with the applications of the compounds in synthesis. It is expected that the combined information will contribute to a deeper understanding of structure/reactivity relationships in this class of heterocycles, with a positive impact in the design of synthetic methods, where they take part.
Topics: Chemistry, Pharmaceutical; Molecular Structure; Pyrazoles; Pyrimidines; Structure-Activity Relationship
PubMed: 31877672
DOI: 10.3390/molecules25010042 -
Current Topics in Medicinal Chemistry 2022Indazoles are a class of heterocyclic compounds with a bicyclic ring structure composed of a pyrazole ring and a benzene ring. Indazole-containing compounds with various... (Review)
Review
Indazoles are a class of heterocyclic compounds with a bicyclic ring structure composed of a pyrazole ring and a benzene ring. Indazole-containing compounds with various functional groups have important pharmacological activities and can be used as structural motifs in designing novel drug molecules. Some of the indazole-containing molecules are approved by FDA and are already in the market. However, very few drugs with indazole rings have been developed against cardiovascular diseases. This review aims to summarize the structural and pharmacological functions of indazole derivatives which have shown efficacy against cardiovascular pathologies in experimental settings.
Topics: Cardiovascular Diseases; Humans; Indazoles; Structure-Activity Relationship
PubMed: 34906057
DOI: 10.2174/1568026621666211214151534 -
Journal of Crohn's & Colitis Aug 2020Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are chronic inflammatory disorders of the gastrointestinal tract which are characterised,... (Review)
Review
Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are chronic inflammatory disorders of the gastrointestinal tract which are characterised, in part, by an imbalance in the production of several pro- and anti-inflammatory cytokines. Although various agents are effective for inducing and maintaining remission, approximately 20% of patients are treatment-refractory and require surgery. Parenterally administered monoclonal antibody-based biologics are associated with adverse effects resulting in treatment discontinuation and/or immunogenicity, leading to loss of response to therapy. Approximately 50% of patients who initially respond to treatment with tumour necrosis factor antagonists lose response to therapy within the 1st year of treatment. Incidence of immunogenicity tends to decrease over time, but once present can persist for years, even after treatment discontinuation. Nonimmunogenic oral small molecule therapies, including Janus kinase inhibitors, are currently being developed and have demonstrated efficacy in early phase clinical trials, which has already led to regulatory approval of tofacitinib for the treatment of patients with moderate-to-severe ulcerative colitis. Differentiation of T cells into T helper cells, which are mediators of the inflammatory response in inflammatory bowel disease, is mediated by the Janus kinase signal transducer and activator of the transcription signalling pathway. Absorption and distribution of Janus kinase inhibitors occurs at the site of action in the gastrointestinal tract, and newer compounds are being developed with limited systemic absorption, potentially reducing the risk of adverse effects. The current review describes the clinical pharmacology of approved Janus kinase inhibitors, as well as those in clinical development for the treatment of inflammatory bowel disease.
Topics: Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Piperidines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Triazoles
PubMed: 32160283
DOI: 10.1093/ecco-jcc/jjaa014 -
International Journal of Molecular... Jul 2020Pyrazolines are five-membered heterocycles possessing two adjacent nitrogens. They have attracted significant attention from organic and medicinal chemists due to their... (Review)
Review
Pyrazolines are five-membered heterocycles possessing two adjacent nitrogens. They have attracted significant attention from organic and medicinal chemists due to their potent biological activities and the numerous possibilities for structural diversification. In the last decade, they have been intensively studied as targets for potential anticancer therapeutics, producing a steady yearly rise in the number of published research articles. Many pyrazoline derivatives have shown remarkable cytotoxic activities in the form of heterocyclic or non-heterocyclic based hybrids, such as with coumarins, triazoles, and steroids. The enormous amount of related literature in the last 5 years prompted us to collect all these published data from screening against cancer cell lines, or protein targets like EGFR and structure activity relationship studies. Therefore, in the present review, a comprehensive account of the compounds containing the pyrazoline nucleus will be provided. The chemical groups and the structural modifications responsible for the activity will be highlighted. Moreover, emphasis will be given on recent examples from the literature and on the work of research groups that have played a key role in the development of this field.
Topics: Antineoplastic Agents; Cell Proliferation; Coumarins; Humans; Molecular Structure; Neoplasms; Nitrogen; Pyrazoles; Steroids; Structure-Activity Relationship; Triazoles
PubMed: 32752126
DOI: 10.3390/ijms21155507 -
Molecules (Basel, Switzerland) May 2024Chronic inflammation contributes to a number of diseases. Therefore, control of the inflammatory response is an important therapeutic goal. To identify novel...
Chronic inflammation contributes to a number of diseases. Therefore, control of the inflammatory response is an important therapeutic goal. To identify novel anti-inflammatory compounds, we synthesized and screened a library of 80 pyrazolo[1,5-]quinazoline compounds and related derivatives. Screening of these compounds for their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor κB (NF-κB) transcriptional activity in human THP-1Blue monocytic cells identified 13 compounds with anti-inflammatory activity (IC < 50 µM) in a cell-based test system, with two of the most potent being compounds (5-[(4-sulfamoylbenzyl)oxy]pyrazolo[1,5-]quinazoline-3-carboxamide) and (5-[(4-(methylsulfinyl)benzyloxy]pyrazolo[1,5-]quinazoline-3-carboxamide). Pharmacophore mapping of potential targets predicted that and may be ligands for three mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 2 (ERK2), p38α, and -Jun -terminal kinase 3 (JNK3). Indeed, molecular modeling supported that these compounds could effectively bind to ERK2, p38α, and JNK3, with the highest complementarity to JNK3. The key residues of JNK3 important for this binding were identified. Moreover, compounds and exhibited micromolar binding affinities for JNK1, JNK2, and JNK3. Thus, our results demonstrate the potential for developing lead anti-inflammatory drugs based on the pyrazolo[1,5-]quinazoline and related scaffolds that are targeted toward MAPKs.
Topics: Humans; Quinazolines; Anti-Inflammatory Agents; NF-kappa B; Lipopolysaccharides; Molecular Docking Simulation; Pyrazoles; Structure-Activity Relationship; THP-1 Cells
PubMed: 38893295
DOI: 10.3390/molecules29112421 -
Molecules (Basel, Switzerland) Dec 2022A general approach towards the synthesis of tetrahydro-4-pyrazolo[1,5-][1,4]diazepin-4-one, tetrahydro[1,4]diazepino[1,2-]indol-1-one and...
A general approach towards the synthesis of tetrahydro-4-pyrazolo[1,5-][1,4]diazepin-4-one, tetrahydro[1,4]diazepino[1,2-]indol-1-one and tetrahydro-1-benzo[4,5]imidazo[1,2-][1,4]diazepin-1-one derivatives was introduced. A regioselective strategy was developed for synthesizing ethyl 1-(oxiran-2-ylmethyl)-1-pyrazole-5-carboxylates from easily accessible 3(5)-aryl- or methyl-1-pyrazole-5(3)-carboxylates. Obtained intermediates were further treated with amines resulting in oxirane ring-opening and direct cyclisation-yielding target pyrazolo[1,5-][1,4]diazepin-4-ones. A straightforward two-step synthetic approach was applied to expand the current study and successfully functionalize ethyl 1-indole- and ethyl 1-benzo[]imidazole-2-carboxylates. The structures of fused heterocyclic compounds were confirmed by H, C, and N-NMR spectroscopy and HRMS investigation.
Topics: Pyrazoles; Cyclization
PubMed: 36557800
DOI: 10.3390/molecules27248666