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Journal of the American College of... Dec 2023
Topics: Child; Humans; Warfarin; Anticoagulants; Heart Diseases; Pyrazoles; Pyridones; Atrial Fibrillation; Stroke; Cost-Benefit Analysis
PubMed: 38057073
DOI: 10.1016/j.jacc.2023.10.011 -
American Journal of Clinical Dermatology Jul 2023Baricitinib (Olumiant), a Janus kinase (JAK) inhibitor, is the first drug approved for the treatment of severe alopecia areata in the USA and the EU. Severe alopecia... (Review)
Review
Baricitinib (Olumiant), a Janus kinase (JAK) inhibitor, is the first drug approved for the treatment of severe alopecia areata in the USA and the EU. Severe alopecia areata is usually difficult to treat and relapse is common. Patients with this disorder are more likely to suffer from anxiety and depression. In two pivotal placebo-controlled phase 3 clinical trials in adults with severe alopecia areata, oral baricitinib once daily was associated with clinically meaningful scalp, eyebrow, and eyelash hair regrowth over 36 weeks. Baricitinib was generally well tolerated with the most common adverse events being infections, headaches, acne, and elevated levels of creatine phosphokinase. While longer-term data will be necessary to more fully understand the benefits and risks of the drug, currently available data suggest that baricitinib is a useful treatment for patients with severe alopecia areata.
Topics: Adult; Humans; Alopecia Areata; Azetidines; Janus Kinase Inhibitors; Pyrazoles; Clinical Trials, Phase III as Topic
PubMed: 37326792
DOI: 10.1007/s40257-023-00799-z -
European Journal of Medicinal Chemistry Sep 2023Chemotherapeutics occupy a pivotal role in the medication of different types of cancers, but the prevalence and mortality rates of cancer remain high. The drug... (Review)
Review
Chemotherapeutics occupy a pivotal role in the medication of different types of cancers, but the prevalence and mortality rates of cancer remain high. The drug resistance and low specificity of current available chemotherapeutics are the main barriers for the effective cancer chemotherapy, evoking an immediate need for the development of novel anticancer agents. Pyrazole is a highly versatile five-membered heterocycle with two adjacent nitrogen atoms and possesses remarkable therapeutic effects and robust pharmacological potency. The pyrazole derivatives especially pyrazole hybrids have demonstrated potent in vitro and in vivo efficacies against cancers through multiple mechanisms, inclusive of apoptosis induction, autophagy regulation, and cell cycle disruption. Moreover, several pyrazole hybrids such as crizotanib (pyrazole-pyridine hybrid), erdafitinib (pyrazole-quinoxaline hybrid) and ruxolitinib (pyrazole-pyrrolo [2,3-d]pyrimidine hybrid) have already been approved for the cancer therapy, revealing that pyrazole hybrids are useful scaffolds to develop novel anticancer agents. The purpose of this review is to summarize the current scenario of pyrazole hybrids with potential in vivo anticancer efficacy along with mechanisms of action, toxicity, and pharmacokinetics, covering papers published in recent 5 years (2018-present), to facilitate further rational exploitation of more effective candidates.
Topics: Humans; Structure-Activity Relationship; Neoplasms; Antineoplastic Agents; Pyrazoles; Azoles
PubMed: 37209450
DOI: 10.1016/j.ejmech.2023.115495 -
Future Medicinal Chemistry Nov 2023Pyrazole or 1-pyrazole, a five-membered 1,2-diazole, is found in several approved drugs and some bioactive natural products. A myriad number of derivatives of this small... (Review)
Review
Pyrazole or 1-pyrazole, a five-membered 1,2-diazole, is found in several approved drugs and some bioactive natural products. A myriad number of derivatives of this small molecule have been reported in clinical and preclinical studies for the potential treatment of several diseases. The number of drugs containing a pyrazole nucleus has increased significantly in the last 10 years. Some of the best-selling drugs in this class are ibrutinib, ruxolitinib, axitinib, niraparib and baricitinib, and are used to treat different types of cancers; lenacapavir to treat HIV; riociguat to treat pulmonary hypertension; and sildenafil to treat erectile dysfunction. Several aniline-derived pyrazole compounds have been reported as potent antibacterial agents with selective activity against methicillin-resistant and vancomycin-resistant enterococci. Here, we discuss the pyrazole-derived drugs reported up to September 2023.
Topics: Male; Humans; Methicillin-Resistant Staphylococcus aureus; Anti-Bacterial Agents; Pyrazoles; Drug Discovery; Microbial Sensitivity Tests
PubMed: 37933613
DOI: 10.4155/fmc-2023-0207 -
Expert Opinion on Pharmacotherapy Apr 2024The introduction of the first JAK inhibitor (JAKi) ruxolitinib 10 years ago represented a pivotal advancement in myelofibrosis (MF) treatment, mostly in terms of... (Review)
Review
INTRODUCTION
The introduction of the first JAK inhibitor (JAKi) ruxolitinib 10 years ago represented a pivotal advancement in myelofibrosis (MF) treatment, mostly in terms of spleen and symptoms response. Nowadays three more JAKi, fedratinib, pacritinib, and momelotinib, are available for both ruxolitinib-resistant and naïve patients. Moreover, many drugs are currently being investigated, both alone and in combination with JAKi.
AREAS COVERED
In this review we discuss the long-term data of ruxolitinib and more recent evidence coming from clinical trials of fedratinib, pacritinib, and momelotinib, used as first- or second-line MF therapy. More, focus is set on data from non-JAKi drugs, such as the quite extensively studied BET-inhibitors (pelabresib) and BCL-inhibitors (navitoclax), novel target therapies, and drugs aimed to improve anemia, still representing a major determinant of reduced survival in MF.
EXPERT OPINION
It's now evident that JAKi monotherapy, though clinically effective, is rarely able to change MF natural history; novel drugs are promising but long-term data are inevitably lacking. We feel that soon MF treatment will require clinicians to select the most appropriate JAKi inhibitor, based on patient characteristics, associating either front-line or in case of early suboptimal response, non-JAKi drugs with the aim to pursue disease modification.
Topics: Humans; Primary Myelofibrosis; Janus Kinase Inhibitors; Nitriles; Pyrimidines; Animals; Molecular Targeted Therapy; Pyrazoles
PubMed: 38738513
DOI: 10.1080/14656566.2024.2354461 -
Journal of Clinical Oncology : Official... Feb 2024
Topics: Humans; Waldenstrom Macroglobulinemia; Piperidines; Pyrazoles; Pyrimidines
PubMed: 38048514
DOI: 10.1200/JCO.23.01881 -
Bioorganic Chemistry Oct 2023Tumor selectivity is yet a challenge in chemotherapy-based cancer treatment. A series of calixarenes derivatized at the lower rim with 3-phenyl-1H-pyrazole units with...
Tumor selectivity is yet a challenge in chemotherapy-based cancer treatment. A series of calixarenes derivatized at the lower rim with 3-phenyl-1H-pyrazole units with variable upper-rim substituent and conformations of macrocyclic core, alkyl chain length between heterocycle and core, as well as phenolic monomer (5-(4-tert-butylphenyloxy)methoxy-3-phenyl-1H-pyrazole) have been synthesized and characterized in a range of therapeutically relevant cellular models (M-HeLa, MCF7, A-549, PC3, Chang liver, and Wi38) from different target organs/systems. Specific cytotoxicity for M-HeLa cells has been observed in tert-butylcalix[4]arene pyrazoles in 1,3-alternate (compound 7b) and partial cone (compound 7c) conformations with low mutagenicity and haemotoxicity and in vivo toxicity in mice. Compounds 7b,c have induced mitochondrial pathway of apoptosis of M-HeLa cells through caspase-9 activation preceded by the cell cycle arrest at G0/G1 phase. A concomitant overexpression of DNA damage markers in pyrazole-treated M-HeLa cells suggests that calixarene pyrazoles target DNA, which was supported by the presence of interactions between calixarenes and ctDNA at the air-water interface.
Topics: Animals; Humans; Mice; Calixarenes; HeLa Cells; Neoplasms; Porifera; Pyrazoles
PubMed: 37480816
DOI: 10.1016/j.bioorg.2023.106742 -
Journal of the European Academy of... Mar 2024Efficacy of the Janus kinase (JAK) inhibitor baricitinib for severe alopecia areata (AA) continuously increased over 52 weeks in two Phase 3 trials. There are limited...
BACKGROUND
Efficacy of the Janus kinase (JAK) inhibitor baricitinib for severe alopecia areata (AA) continuously increased over 52 weeks in two Phase 3 trials. There are limited long-term data on JAK inhibitors in AA.
OBJECTIVES
To evaluate efficacy and safety of baricitinib for severe AA through 104 weeks of continuous therapy.
METHODS
Integrated data from the BRAVE-AA1 and BRAVE-AA2 Phase 3 trials included adults with Severity of Alopecia Tool (SALT) scores ≥50 (≥50% scalp hair loss) randomized to and continuously treated with 2-mg or 4-mg baricitinib through Week 104. Patients who qualified to remain on continuous treatment included subjects who achieved SALT score ≤20 at Week 52 (Week-52 responders; 2-mg: N = 65; 4-mg: N = 129) and baricitinib 4-mg-treated patients who had SALT score >20 at Week 52 but achieved SALT score ≤20 at prior visit(s) and/or had significant improvement in eyebrow or eyelash hair growth relative to baseline by Week 52 (Week-52 mixed responders; N = 110). Week-104 outcomes included the proportion of patients achieving SALT score ≤20 (≤20% scalp hair loss). Data were censored after treatment discontinuation.
RESULTS
Among baricitinib 4-mg-treated and baricitinib 2-mg-treated Week-52 responders, 90.7% and 89.2%, respectively, maintained SALT score ≤20 at Week 104. Among Week-52 mixed responders, 39.1% reached SALT score ≤20 by Week 104. Continued improvement in eyebrow and eyelash regrowth was observed across groups. The most frequent treatment-emergent adverse events were COVID-19, upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection and creatine phosphokinase increase.
CONCLUSIONS
Baricitinib demonstrated a high level of maintenance of efficacy over 104 weeks in patients with severe AA. Efficacy increased in Week-52 mixed responders, illustrating that long-term treatment is necessary to observe maximum benefit in some patients. No new safety signals were observed.
Topics: Adult; Humans; Alopecia; Alopecia Areata; Azetidines; Janus Kinase Inhibitors; Purines; Pyrazoles; Sulfonamides; Randomized Controlled Trials as Topic; Clinical Trials, Phase III as Topic
PubMed: 38391212
DOI: 10.1111/jdv.19665 -
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 -
Chemistry & Biodiversity Aug 2023In this study, we designed and synthesized 19 nitrogen-containing heterocyclic derivatives of panaxadiol (PD). We first reported the antiproliferative activity of these...
In this study, we designed and synthesized 19 nitrogen-containing heterocyclic derivatives of panaxadiol (PD). We first reported the antiproliferative activity of these compounds against four different tumor cells. The results of the MTT assay showed that the PD pyrazole derivative (compound 12b) had the best antitumor activity and could significantly inhibit the proliferation of four tested tumor cells. For A549 cells, the IC value was as low as 13.44±1.23 μM. Western blot analysis showed that the PD pyrazole derivative was a bifunctional regulator. On the one hand, it can down-regulate the expression of HIF-1α by acting on PI3 K/AKT signaling pathway in A549 cells. On the other hand, it can induce the decrease of CDKs protein family and E2F1 protein expression levels, thus playing a crucial role in cell cycle arrest. According to the results of molecular docking, we found that multiple hydrogen bonds were formed between the PD pyrazole derivative and two related proteins, and the docking score of the derivative was also significantly higher than that of the crude drug. In summary, the study of the PD pyrazole derivative laid a foundation for the development of ginsenoside as an antitumor agent.
Topics: Structure-Activity Relationship; Ginsenosides; Cell Line, Tumor; Molecular Docking Simulation; Cell Proliferation; Antineoplastic Agents; Pyrazoles; Drug Screening Assays, Antitumor; Molecular Structure; Apoptosis
PubMed: 37279052
DOI: 10.1002/cbdv.202300507