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Scientific Reports May 2023F508del, the most frequent mutation in cystic fibrosis (CF), impairs the stability and folding of the CFTR chloride channel, thus resulting in intracellular retention...
F508del, the most frequent mutation in cystic fibrosis (CF), impairs the stability and folding of the CFTR chloride channel, thus resulting in intracellular retention and CFTR degradation. The F508del defect can be targeted with pharmacological correctors, such as VX-809 and VX-445, that stabilize CFTR and improve its trafficking to plasma membrane. Using a functional test to evaluate a panel of chemical compounds, we have identified tricyclic pyrrolo-quinolines as novel F508del correctors with high efficacy on primary airway epithelial cells from CF patients. The most effective compound, PP028, showed synergy when combined with VX-809 and VX-661 but not with VX-445. By testing the ability of correctors to stabilize CFTR fragments of different length, we found that VX-809 is effective on the amino-terminal portion of the protein that includes the first membrane-spanning domain (amino acids 1-387). Instead, PP028 and VX-445 only show a stabilizing effect when the second membrane-spanning domain is included (amino acids 1-1181). Our results indicate that tricyclic pyrrolo-quinolines are a novel class of CFTR correctors that, similarly to VX-445, interact with CFTR at a site different from that of VX-809. Tricyclic pirrolo-quinolines may represent novel CFTR correctors suitable for combinatorial pharmacological treatments to treat the basic defect in CF.
Topics: Humans; Cystic Fibrosis Transmembrane Conductance Regulator; Chloride Channels; Quinolines; Cystic Fibrosis; Benzodioxoles; Aminopyridines; Mutation
PubMed: 37165082
DOI: 10.1038/s41598-023-34440-0 -
Molecules (Basel, Switzerland) Mar 2022A short and economical synthesis of various 2-methylaminopyidine amides (MAPA) from 2-bromopyridine has been developed using the catalytic Goldberg reaction. The...
A short and economical synthesis of various 2-methylaminopyidine amides (MAPA) from 2-bromopyridine has been developed using the catalytic Goldberg reaction. The effective catalyst was formed in situ by the reaction of CuI and 1,10-phenanthroline in a 1/1 ratio with a final loading of 0.5-3 mol%. The process affords high yields and can accommodate multigram-scale reactions. A modification of this method provides a new preparation of 2--substituted aminopyridines from various secondary -alkyl(aryl)formamides and 2-bromopyridine. The intermediate aminopyridine formamide is cleaved in situ through methanolysis or hydrolysis to give 2-alkyl(aryl)aminopyridines in high yields.
Topics: Amides; Aminopyridines; Catalysis; Hydrolysis; Indicators and Reagents
PubMed: 35335206
DOI: 10.3390/molecules27061833 -
Indian Journal of Dermatology,... 2021
Topics: Administration, Topical; Aminopyridines; Anti-Bacterial Agents; Contraindications, Drug; Drug Interactions; Drug Resistance, Bacterial; Humans; Molecular Structure; Ointments; Quinolones
PubMed: 33580932
DOI: 10.25259/IJDVL_191_20 -
The Journal of Pharmacology and... Jan 2024Botulinum neurotoxin (BoNT) is a potent protein toxin that causes muscle paralysis and death by asphyxiation. Treatments for symptomatic botulism are intubation and...
Botulinum neurotoxin (BoNT) is a potent protein toxin that causes muscle paralysis and death by asphyxiation. Treatments for symptomatic botulism are intubation and supportive care until respiratory function recovers. Aminopyridines have recently emerged as potential treatments for botulism. The clinically approved drug 3,4-diaminopyridine (3,4-DAP) rapidly reverses toxic signs of botulism and has antidotal effects when continuously administered in rodent models of lethal botulism. Although the therapeutic effects of 3,4-DAP likely result from the reversal of diaphragm paralysis, the corresponding effects on respiratory physiology are not understood. Here, we combined unrestrained whole-body plethysmography (UWBP) with arterial blood gas measurements to study the effects of 3,4-DAP, and other aminopyridines, on ventilation and respiration at terminal stages of botulism in mice. Treatment with clinically relevant doses of 3,4-DAP restored ventilation in a dose-dependent manner, producing significant improvements in ventilatory parameters within 10 minutes. Concomitant with improved ventilation, 3,4-DAP treatment reversed botulism-induced respiratory acidosis, restoring blood levels of CO, pH, and lactate to normal physiologic levels. Having established that 3,4-DAP-mediated improvements in ventilation were directly correlated with improved respiration, we used UWBP to quantitatively evaluate nine additional aminopyridines in BoNT/A-intoxicated mice. Multiple aminopyridines were identified with comparable or enhanced therapeutic efficacies compared with 3,4-DAP, including aminopyridines that selectively improved tidal volume versus respiratory rate and vice versa. In addition to contributing to a growing body of evidence supporting the use of aminopyridines to treat clinical botulism, these data lay the groundwork for the development of aminopyridine derivatives with improved pharmacological properties. SIGNIFICANCE STATEMENT: There is a critical need for fast-acting treatments to reverse respiratory paralysis in patients with botulism. This study used unrestrained, whole-body plethysmography and arterial blood gas analysis to show that aminopyridines rapidly restore ventilation and respiration and reverse respiratory acidosis when administered to mice at terminal stages of botulism. In addition to supporting the use of aminopyridines as first-line treatments for botulism symptoms, these data are expected to contribute to the development of new aminopyridine derivatives with improved pharmacological properties.
Topics: Mice; Humans; Animals; Botulism; Aminopyridines; Amifampridine; Acidosis, Respiratory; Botulinum Toxins, Type A; Paralysis; Respiration
PubMed: 37977816
DOI: 10.1124/jpet.123.001773 -
Journal of Thoracic Oncology : Official... Jan 2023
Topics: Humans; Lung Neoplasms; Lactams, Macrocyclic; Lactams; Aminopyridines; Protein Kinase Inhibitors
PubMed: 36543433
DOI: 10.1016/j.jtho.2022.11.003 -
The Yale Journal of Biology and Medicine Dec 2020Amlexanox, a small molecule targeted therapy which has been used in the treatment of atopic conditions was previously but is not currently available in the United... (Review)
Review
Amlexanox, a small molecule targeted therapy which has been used in the treatment of atopic conditions was previously but is not currently available in the United States. Amlexanox has also been legally utilized and administered in Japan as a treatment for asthma, a chronic pulmonary disease characterized by inflammation of the lower respiratory tract. Amlexanox's immune modulatory effects have been the subject of studies which have repurposed the drug for potential therapeutic applications in metabolic and inflammatory disease. Because amlexanox inhibits TANK-binding kinase1 (TBK1) and nuclear factor kB kinase epsilon (IKKε), several studies have demonstrated its usefulness through its evidence downregulation of the immune system and attenuation of downstream TBK1 signaling. Novel therapies, such as amlexanox, for inflammatory conditions such as asthma will continue to be of value in clinical management. This report summarizes key applications of the drug based on animal and human studies and explores its potential in treatment of metabolic and inflammatory diseases.
Topics: Aminopyridines; Animals; Anti-Allergic Agents; Asthma; Humans; Hypersensitivity, Immediate; Inflammation; Japan; Signal Transduction
PubMed: 33380937
DOI: No ID Found -
Annals of Oncology : Official Journal... Mar 2022
Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Female; Humans; Ki-67 Antigen
PubMed: 34942341
DOI: 10.1016/j.annonc.2021.12.004 -
Journal of Thrombosis and Haemostasis :... Apr 2023Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors are an essential treatment modality for hormone receptor-positive breast cancer. As the rates of breast cancer continue... (Review)
Review
Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors are an essential treatment modality for hormone receptor-positive breast cancer. As the rates of breast cancer continue to rise globally and the indications for CDK 4/6 inhibitors now extend beyond metastatic disease, more patients than ever are receiving these agents. Thrombosis is an emerging clinical concern with this class of agents, particularly venous thromboembolism. Although venous thromboembolism initially emerged as an adverse effect of interest in early trials, more recent studies have demonstrated even higher incidences of thrombosis in real-world clinical practice. In this review, we summarize the evidence to date that has informed the thrombosis risk for these agents both in clinical trials and real-world studies. We review data describing the venous and arterial thromboembolic risks in clinical trials of CDK 4/6 inhibitors as well as the now rather extensive real-world evidence available, including a comparison of risk for each of the 3 agents approved for use in breast cancer: palcociclib, ribociclib, and abemaciclib. As the role of prophylactic anticoagulation continues to remain unknown in women receiving CDK 4/6 inhibitors, future efforts directed at carefully investigating the risks and benefits of thromboprophylaxis may lead to improved outcomes in these patients.
Topics: Humans; Female; Pyridines; Cyclin-Dependent Kinase 4; Venous Thromboembolism; Anticoagulants; Protein Kinase Inhibitors; Aminopyridines; Breast Neoplasms
PubMed: 36696184
DOI: 10.1016/j.jtha.2022.12.001 -
Swiss Medical Weekly 2012Roflumilast is a selective phosphodiesterase 4 inhibitor which has been licensed in the European Union since 2010 and in Switzerland since November 2011 as an add-on... (Review)
Review
Roflumilast is a selective phosphodiesterase 4 inhibitor which has been licensed in the European Union since 2010 and in Switzerland since November 2011 as an add-on treatment for patients with chronic obstructive pulmonary disease (COPD) in GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages 3 and 4 (FEV(1) <50% predicted after bronchodilatation) and frequent exacerbations despite correctly-dosed therapy with a long-acting bronchodilator. Roflumilast is designed to target both the systemic and pulmonary inflammation associated with COPD. In this review roflumilast's chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy, safety and tolerability and the current ongoing clinical trials involving roflumilast are outlined. Information has been sourced from the Swiss and US product information monographs, peer-reviewed published literature (identified from a PubMed MEDLINE search 1966 - March 2012 using the term "roflumilast"), the COPD GOLD international guidelines for the management of COPD (Revised 2011) and an independent analysis of phase 3 clinical trial data by FDA staff physicians. Clinical efficacy in terms of a modest gain in FEV(1)% and a reduction in exacerbation rate has been demonstrated in phase 3 clinical trials and roflumilast has been recently incorporated into international treatment guidelines. However data examining roflumilast as add-on therapy to long-acting bronchodilators and ICS (standard therapy) is currently awaited and phase 4 post-marketing studies are required to determine the incidence and severity of adverse events and the long-term beneficial effects of roflumilast as a maintenance therapy for COPD in every-day clinical practice.
Topics: Aminopyridines; Benzamides; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Humans; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index
PubMed: 22833385
DOI: 10.4414/smw.2012.13628 -
Pulmonary Pharmacology & Therapeutics Feb 2021The recent pandemic of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an extraordinary challenge to identify... (Review)
Review
The recent pandemic of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an extraordinary challenge to identify effective drugs for prevention and treatment. The pathogenesis implicate acute respiratory disorder (ARD) which is attributed to significantly triggered "cytokine storm" and compromised immune system. This article summarizes the likely benefits of roflumilast, a Phosphodiesterase-4 (PDE-4) inhibitor as a comprehensive support COVID-19 pathogenesis. Roflumilast, a well-known anti-inflammatory and immunomodulatory drug, is protective against respiratory models of chemical and smoke induced lung damage. There is significant data which demonstrate the protective effect of PDE-4 inhibitor in respiratory viral models and is likely to be beneficial in combating COVID-19 pathogenesis. Roflumilast is effective in patients with severe COPD by reducing the rate of exacerbations with the improvement of the lung function, which might further be beneficial for better clinical outcomes in COVID-19 patients. However, further clinical trials are warranted to examine this conjecture.
Topics: Aminopyridines; Anti-Inflammatory Agents; Benzamides; COVID-19; Cyclopropanes; Cytokines; Inflammation Mediators; Pandemics; Phosphodiesterase 4 Inhibitors; COVID-19 Drug Treatment
PubMed: 33259924
DOI: 10.1016/j.pupt.2020.101978