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Journal For Immunotherapy of Cancer Apr 2022Immune-checkpoint inhibitors (ICI) have revolutionized cancer therapy but are associated with infrequent but lethal myocarditis, for which management remains uncertain....
Immune-checkpoint inhibitors (ICI) have revolutionized cancer therapy but are associated with infrequent but lethal myocarditis, for which management remains uncertain. Abatacept, a CTLA-4 fusion protein targeting CD86 on antigen presenting cells and leading to global T-cell anergy, has been described as a potential treatment in individual reports. Yet, abatacept treatment dosage, schedule and optimal combination with other immunosuppressive therapies are unclear. We describe a 25-year-old man who developed pembrolizumab (anti-PD1)-induced myocarditis 14 days after first injection for thymoma treatment, which deteriorated into cardiogenic shock, with sustained ventricular arrhythmia, requiring urgent extracorporeal life support implantation, despite prompt initiation of corticosteroids and mycophenolate-mofetil. Using a strategy of serial measurement ensuring with a target of >80% CD86 receptor occupancy on circulating monocytes, abatacept dose was adjusted and combined with ruxolitinib and methylprednisolone. This strategy resulted in high-dose of abatacept: 60 mg/kg in three doses (20 mg/kg each) within the first 10 days, followed by two doses. Clinical improvement occurred within 7 days, with resolution of systolic cardiac dysfunction, and ventricular arrhythmias resulting in successful discharge from hospital. We reversed a case of nearly lethal ICI-myocarditis, using specific patient-dose adjusted abatacept, which may serve as basis for personalized treatment of patients with severe ICI-adverse events. Trial registration number: NCT04294771.
Topics: Abatacept; Adult; Humans; Immune Checkpoint Inhibitors; Male; Myocarditis; Nitriles; Pyrazoles; Pyrimidines
PubMed: 35383117
DOI: 10.1136/jitc-2022-004699 -
Cells Jul 2022Integrins are adhesion molecules that function as anchors in retaining tumor cells in supportive tissues and facilitating metastasis. Beta1 integrins are known to... (Review)
Review
Integrins are adhesion molecules that function as anchors in retaining tumor cells in supportive tissues and facilitating metastasis. Beta1 integrins are known to contribute to cell adhesion-mediated drug resistance in cancer. Very late antigen-4 (VLA-4), a CD49d/CD29 heterodimer, is a beta1 integrin implicated in therapy resistance in both solid tumors and haematological malignancies such as chronic lymphocytic leukemia (CLL). A complex inside-out signaling mechanism activates VLA-4, which might include several therapeutic targets for CLL. Treatment regimens for this disease have recently shifted towards novel agents targeting BCR signaling. Bruton's tyrosine kinase (BTK) is a component of B cell receptor signaling and BTK inhibitors such as ibrutinib are highly successful; however, their limitations include indefinite drug administration, the development of therapy resistance, and toxicities. VLA-4 might be activated independently of BTK, resulting in an ongoing interaction of CD49d-expressing leukemic cells with their surrounding tissue, which may reduce the success of therapy with BTK inhibitors and increases the need for alternative therapies. In this context, we discuss the inside-out signaling cascade culminating in VLA-4 activation, consider the advantages and disadvantages of BTK inhibitors in CLL and elucidate the mechanisms behind cell adhesion-mediated drug resistance.
Topics: Agammaglobulinaemia Tyrosine Kinase; Humans; Integrin alpha4beta1; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Kinase Inhibitors; Pyrazoles
PubMed: 35883678
DOI: 10.3390/cells11142235 -
International Journal of Molecular... Dec 2023The review focuses on recent advances in the methodologies for the formation or introduction of the CHF moiety in -heterocyclic substrates over the past 5 years. The... (Review)
Review
The review focuses on recent advances in the methodologies for the formation or introduction of the CHF moiety in -heterocyclic substrates over the past 5 years. The monofluoromethyl group is one of the most versatile fluorinated groups used to modify the properties of molecules in synthetic medical chemistry. The review summarizes two strategies for the monofluoromethylation of -containing heterocycles: direct monofluoromethylation with simple XCHF sources (for example, ICHF) and the assembly of -heterocyclic structures from CHF-containing substrates. The review describes the monofluoromethylation of pharmaceutically important three-, five- and six-membered -heterocycles: pyrrolidines, pyrroles, indoles, imidazoles, triazoles, benzothiazoles, carbazoles, indazoles, pyrazoles, oxazoles, piperidines, morpholines, pyridines, quinolines and pyridazines. Assembling of 6-fluoromethylphenanthridine, 5-fluoromethyl-2-oxazolines, C5-monofluorinated isoxazoline -oxides, and α-fluoromethyl-α-trifluoromethylaziridines is also shown. Fluoriodo-, fluorchloro- and fluorbromomethane, FCHSOCl, monofluoromethyl(aryl)sulfoniummethylides, monofluoromethyl sulfides, (fluoromethyl)triphenylphosphonium iodide and 2-fluoroacetic acid are the main fluoromethylating reagents in recent works. The replacement of atoms and entire functional groups with a fluorine atom(s) leads to a change and often improvement in activity, chemical or biostability, and pharmacokinetic properties. The monofluoromethyl group is a bioisoster of -CH, -CHOH, -CHNH, -CHCH, -CHNO and -CHSH moieties. Bioisosteric replacement with the CHF group is both an interesting task for organic synthesis and a pathway to modify drugs, agrochemicals and useful intermediates.
Topics: Imidazoles; Pyrazoles; Pyridines; Piperidines
PubMed: 38139426
DOI: 10.3390/ijms242417593 -
Molecules (Basel, Switzerland) Jun 2021The five-membered heterocyclic group of pyrazoles/pyrazolines plays important role in drug discovery. Pyrazoles and pyrazolines present a wide range of biological...
The five-membered heterocyclic group of pyrazoles/pyrazolines plays important role in drug discovery. Pyrazoles and pyrazolines present a wide range of biological activities. The synthesis of the pyrazolines and pyrazole derivatives was accomplished the condensation of the appropriate substituted aldehydes and acetophenones, suitable chalcones and hydrazine hydrate in absolute ethanol in the presence of drops of glacial acetic acid. The compounds are obtained in good yields 68-99% and their structure was confirmed using IR, H-NMR, C-NMR and elemental analysis. The novel derivatives were studied for their antioxidant, anti-lipid peroxidation (AAPH) activities and inhibitory activity of lipoxygenase. Both classes strongly inhibit lipid peroxidation. Compound was the most potent lipoxygenase inhibitor (IC = 80 µM). The inhibition of the carrageenin-induced paw edema (CPE) and nociception was also determined, with compounds and being the most potent. Compound inhibited nociception higher than . Pyrazoline was found to be active in a preliminary test, for the investigation of anti-adjuvant-induced disease (AID) activity. Pyrazoline derivatives were found to be more potent than pyrazoles. Docking studies of the most potent LOX inhibitor highlight hydrophobic interactions with VAL126, PHE143, VAL520 and LYS526 and a halogen bond between the chlorine atom and ARG182.
Topics: Animals; Anti-Inflammatory Agents; Inhibitory Concentration 50; Lipid Peroxidation; Lipoxygenase; Lipoxygenase Inhibitors; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Protein Binding; Pyrazoles; Rats
PubMed: 34198914
DOI: 10.3390/molecules26113439 -
Molecules (Basel, Switzerland) Mar 2020The present review presents an overview of antitumor pyrazoles of natural or bioinspired origins. Pyrazole compounds are relatively rare in nature, the first ones having... (Review)
Review
The present review presents an overview of antitumor pyrazoles of natural or bioinspired origins. Pyrazole compounds are relatively rare in nature, the first ones having been reported in 1966 and being essentially used as somniferous drugs. Cytotoxic pyrazoles of natural sources were first isolated in 1969, and a few others have been reported since then, most of them in the last decade. This paper presents a perspective on the current knowledge on antitumor natural pyrazoles, organized into two sections. The first focuses on the three known families of cytotoxic pyrazoles that were directly isolated from plants, for which the knowledge of the medicinal properties is in its infancy. The second section describes pyrazole derivatives of natural products, discussing their structure-activity relationships.
Topics: Animals; Antineoplastic Agents; Biological Products; Biomimetic Materials; Humans; Pyrazoles
PubMed: 32192149
DOI: 10.3390/molecules25061364 -
Molecules (Basel, Switzerland) Aug 2021Pyrazoles are considered privileged scaffolds in medicinal chemistry. Previous reviews have discussed the importance of pyrazoles and their biological activities;... (Review)
Review
Pyrazoles are considered privileged scaffolds in medicinal chemistry. Previous reviews have discussed the importance of pyrazoles and their biological activities; however, few have dealt with the chemistry and the biology of heteroannulated derivatives. Therefore, we focused our attention on recent topics, up until 2020, for the synthesis of pyrazoles, their heteroannulated derivatives, and their applications as biologically active moieties. Moreover, we focused on traditional procedures used in the synthesis of pyrazoles.
Topics: Chemistry Techniques, Synthetic; Humans; Pyrazoles
PubMed: 34443583
DOI: 10.3390/molecules26164995 -
Molecules (Basel, Switzerland) May 2023Regio- and stereoselective switchable synthesis of ()- and ()--carbonylvinylated pyrazoles is first developed by using the Michael addition reaction of pyrazoles and...
Regio- and stereoselective switchable synthesis of ()- and ()--carbonylvinylated pyrazoles is first developed by using the Michael addition reaction of pyrazoles and conjugated carbonyl alkynes. AgCO plays a key role in the switchable synthesis of ()- and ()--carbonylvinylated pyrazoles. AgCO-free reactions lead to thermodynamically stable ()--carbonylvinylated pyrazoles in excellent yields whereas reactions with AgCO give ()--carbonylvinylated pyrazoles in good yields. It is noteworthy that ()- or ()--carbonylvinylated pyrazoles are obtained with high regioselectivity when asymmetrically substituted pyrazoles react with conjugated carbonyl alkynes. The method can also extend to the gram scale. A plausible mechanism is proposed on the basis of the detailed studies, wherein Ag acts as coordination guidance.
Topics: Pyrazoles; Stereoisomerism; Catalysis; Alkynes
PubMed: 37298822
DOI: 10.3390/molecules28114347 -
Neuropsychopharmacology Reports Sep 2023This phase 1 study assessed the pharmacokinetics, safety, and tolerability of zuranolone in Japanese and White healthy adults, and Japanese healthy elderly subjects. (Randomized Controlled Trial)
Randomized Controlled Trial
AIM
This phase 1 study assessed the pharmacokinetics, safety, and tolerability of zuranolone in Japanese and White healthy adults, and Japanese healthy elderly subjects.
METHODS
This single-center study consisted of three parts. In Part A (randomized, double-blind), the safety, tolerability, and pharmacokinetics of single dose and 7-day consecutive multiple doses of zuranolone 10, 20, and 30 mg and placebo were assessed in 36 Japanese adults, 24 White adults, and 12 Japanese elderly (aged 65-75 years) subjects. In Part B (randomized, open-label, crossover), the effect of food intake on the pharmacokinetics and safety of single-dose zuranolone 30 mg was evaluated in 12 Japanese adults. In Part C (randomized, double-blind, crossover), the effects of single-dose zuranolone 10 and 30 mg and placebo on electroencephalography parameters were evaluated in eight Japanese adults.
RESULTS
Single and multiple doses of zuranolone were safe and well tolerated in all subjects. Linear pharmacokinetics were observed in the studied dose range. Time to steady-state plasma concentration was within 72 h for Japanese and White adults. Pharmacokinetic profiles were comparable between Japanese and White adults and between Japanese adults and Japanese elderly subjects. Plasma exposures of zuranolone were greater in the fed versus fasted state. Single-dose zuranolone 30 mg increased low-beta electroencephalography power.
CONCLUSION
In healthy Japanese subjects, zuranolone was well tolerated; pharmacokinetic profile was unaffected by ethnicity or age; plasma exposures were greater in the fed state. The increased low-beta electroencephalography power with the 30-mg dose is consistent with γ-aminobutyric acid receptor type A activation by zuranolone.
Topics: Adult; Aged; Humans; East Asian People; Healthy Volunteers; Pyrazoles; White People
PubMed: 37366077
DOI: 10.1002/npr2.12359 -
Blood Aug 2022
Topics: Janus Kinase Inhibitors; Nitriles; Pyrazoles; Pyrimidines; Retrospective Studies
PubMed: 36006674
DOI: 10.1182/blood.2022017056 -
Arquivos Brasileiros de Cardiologia Jul 2022
Topics: Chronic Disease; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines
PubMed: 35830109
DOI: 10.36660/abc.20220305