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After an acute coronary syndrome (ACS), patients with diabetes remain at high risk for additional cardiovascular events despite use of current therapies. Bromodomain and extra-terminal (BET) proteins are epigenetic modulators of inflammation, thrombogenesis, and lipoprotein metabolism implicated in atherothrombosis. The BETonMACE trial tests the hypothesis that treatment with apabetalone, a selective BET protein inhibitor, will improve cardiovascular outcomes in patients with diabetes after an ACS. Patients (n = 2425) with ACS in the preceding 7 to 90 days, with type 2 diabetes and low HDL cholesterol (≤40 mg/dl for men, ≤45 mg/dl for women), receiving intensive or maximum-tolerated therapy with atorvastatin or rosuvastatin, were assigned in double-blind fashion to receive apabetalone 100 mg orally twice daily or matching placebo. Baseline characteristics include female sex (25%), myocardial infarction as index ACS event (74%), coronary revascularization for index ACS (80%), treatment with dual anti-platelet therapy (87%) and renin-angiotensin system inhibitors (91%), median LDL cholesterol 65 mg per deciliter, and median HbA1c 7.3%. The primary efficacy measure is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or stroke. Assumptions include a primary event rate of 7% per annum in the placebo group and median follow-up of 1.5 years. Patients will be followed until at least 250 primary endpoint events have occurred, providing 80% power to detect a 30% reduction in the primary endpoint with apabetalone. BETonMACE will determine whether the addition of the selective BET protein inhibitor apabetalone to contemporary standard of care for ACS reduces cardiovascular morbidity and mortality in patients with type 2 diabetes. Results are expected in 2019.

To update overall survival (OS) results from a previous network meta analysis comparing the relative clinical efficacy of epidermal growth factor receptor-targeted tyrosine kinase inhibitors ( TKIs) for mutation positive ( +) advanced non-small-cell lung cancer (NSCLC). A Bayesian network meta analysis was conducted using updated/mature randomized controlled trial OS results in response to first-line TKI therapies. Dacomitinib showed a numerical improvement of OS relative to other TKIs: afatinib (hazard ratio [HR]: 0.87; 95% credible interval [CrI]: 0.61–1.24), erlotinib (HR: 0.79; 95% CrI: 0.44–1.42), gefitinib (HR: 0.75; 95% CrI: 0.59–0.95) and osimertinib (HR: 0.94; 95% CrI: 0.68–1.29). Dacomitinib should be considered as a first-line treatment option for patients diagnosed with advanced + NSCLC.

Purpose This study evaluated the effect of a single 45-mg dose of dacomitinib (PF-00299804), an irreversible small-molecule inhibitor of human epidermal growth factor receptors-1, -2, and -4, on CYP2D6 activity in healthy volunteers (HV) using dextromethorphan (DM), a selective CYP2D6 probe. Methods Fourteen male HVs were enrolled in this open-label, randomized, cross-over, single-dose study of DM alone or with dacomitinib. Each HV received both treatments separated by a 14-day washout period. The pharmacokinetics of DM, dextrorphan (DX; the major DM metabolite), dacomitinib and PF-05199265 (an active metabolite of dacomitinib) were calculated. Results When combined with dacomitinib, the ratio of adjusted geometric means (90% CI) of DM area under the concentration–time curve (AUC) last was 955% (90% CI: 560%, 1,630%) and maximum plasma concentration ( C max ) was 973% (90% CI: 590%, 1,606%), compared with DM alone. For dacomitinib plus DM, exposures were consistent with those in patients receiving single-dose dacomitinib. Terminal elimination half-life ( t 1/2 ) was 51.4 h. Mild and moderate treatment-related adverse events were reported. No HV withdrew from the study. Conclusions Single-dose administration of dacomitinib plus DM was safe and well tolerated in HVs and resulted in a significant increase in systemic exposures of DM in extensive metabolizers. No effect was observed on the pharmacokinetics of dacomitinib. Drug–drug interaction may occur when dacomitinib is concomitantly administered with therapeutic agents metabolized by cytochrome P450 (CYP) 2D6. Administration of drugs which are highly dependent on CYP2D6 metabolism may require dose adjustment, or substitution with an alternative medication.

Quinazolines are nitrogen-containing heterocycles that consist of a benzene ring fused with a pyrimidine ring. Quinazolinones, oxidized quinazolines, are promising compounds with a wide range of biological activities. In the pharmaceutical field, quinazolinones are the building blocks of more than 150 naturally occurring alkaloids isolated from different plants, microorganisms, and animals. Scientists give a continuous interest in this moiety due to their stability and relatively easy methods for preparation. Their lipophilicity is another reason for this interest as it helps quinazolinones in penetration through the blood–brain barrier which makes them suitable for targeting different central nervous system diseases. Various modifications to the substitutions around the quinazolinone system changed their biological activity significantly due to changes in their physicochemical properties. Structure–activity relationship (SAR) studies of quinazolinone revealed that positions 2, 6, and 8 of the ring systems are significant for different pharmacological activities. In addition, it has been suggested that the addition of different heterocyclic moieties at position 3 could increase activity. In this review, we will highlight the chemical properties of quinazolinones, including their chemical reactions and different methods for their preparation. Moreover, we will try to modify some of the old SAR studies according to their updated biological activities in the last twelve years.

Background ARCHER 1050, an ongoing, randomized, open-label, phase III trial of dacomitinib versus gefitinib in newly diagnosed patients with advanced non-small-cell lung cancer (NSCLC) and an EGFR -activating mutation, reported significant improvement in overall survival (OS) with dacomitinib. Objective This paper reports an updated OS analysis of ARCHER 1050 after an extended follow-up. Patients and methods In this multinational, multicenter trial, adults (aged ≥ 18 years or ≥ 20 years in Japan and Korea) with newly diagnosed NSCLC and EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and no history of central nervous system metastases, were randomized 1:1 to receive dacomitinib 45 mg/day ( n  = 227) or gefitinib 250 mg/day ( n  = 225). Randomization was stratified by race and EGFR mutation type. An ad hoc updated analysis of OS was conducted at the protocol-defined cut-off of 48 months from first dosing of the last enrolled patient (13 May 2019). Results After a median follow-up of 47.9 months, 133 (58.6%) patients had died in the dacomitinib arm and 152 (67.6%) in the gefitinib arm. The hazard ratio (HR) for OS was 0.748 (95% CI 0.591–0.947; two-sided P  = 0.0155); median OS was 34.1 months with dacomitinib versus 27.0 months with gefitinib. The HR for OS in patients with dose reduction(s) in the dacomitinib arm ( n  = 154) compared with all patients in the gefitinib arm was 0.554 (95% CI 0.420–0.730); median OS was 42.5 months for patients with dose reduction(s) in the dacomitinib arm. The most common adverse events were diarrhea (87.7%), paronychia (61.7%), dermatitis acneiform (49.3%), and stomatitis (43.6%) with dacomitinib, and diarrhea (55.8%) and alanine aminotransferase increased (40.2%) with gefitinib. Conclusions The OS benefit from first-line treatment with dacomitinib versus gefitinib was maintained after extended follow-up in patients with advanced NSCLC with EGFR -activating mutations. ClinicalTrials.gov NCT01774721 (registered 24 January 2013).

Quinazolinones, essential quinazoline derivatives, exhibit diverse biological activities with applications in pharmaceuticals and insecticides. Some derivatives have already been developed as commercial drugs. Given the rising cancer incidence, there is a critical need for new anticancer agents, and quinazolinones show promising potential in this domain. The present review focuses on novel advances in the synthesis of these important scaffolds and other medicinal aspects involving drug design, the structure-activity relationship, and action mechanisms of quinazoline and quinazolinone derivatives, to help in the development of new quinazoline and quinazolinone derivatives.

Diabetes can cause serious complications such as liver damage and nerve pain. Unfortunately, existing treatment options for these problems often have limited effectiveness and unwanted side effects. To find better therapeutic alternatives with good efficacy and safety profile this study tested a novel quinazolinone derivative, (E)-1-benzoyl-3-((4(dimethylamino)benzylidene)amino)-2-(4-(dimethylamino)phenyl)-2,3 dihydroquinazoline-4(1H)-one , in diabetic mice’s experiencing liver damage and neuropathic pain. Diabetes was induced in mice using alloxan (150 mg/kg). For possible antidiabetic effect, test compound was given in doses of 10 mg/kg and 20 mg/kg. The standard drugs used for comparison was Glibenclamide (5 mg/kg), Tramadol (50 mg/kg) and Diclofenac sodium (50 mg/kg) for pain relief, and Gabapentin (75 mg/kg) for nerve pain. Pain relieving effect was assessed using various test models (e.g., hot plate, writhing, allodynia, and hyperalgesia). Liver function was studied through blood tests and tissue examination. The test compound (at test dose of 20 mg/kg) led to a significant reduction in blood glucose even greater than the reduction seen with glibenclamide (5 mg/kg). Similarly, the test compound significantly reduced pain and showed protective effects on the liver. This new quinazolinone compound was found to be safe and effective in reducing diabetic nerve pain and liver damage in mice. It may offer a better alternative to currently available treatments like gabapentin and glibenclamide.

Bacterial signaling systems are prime drug targets for combating the global health threat of antibiotic resistant bacterial infections including those caused by Staphylococcus aureus. S. aureus is the primary cause of acute bacterial skin and soft tissue infections (SSTIs) and the quorum sensing operon agr is causally associated with these. Whether efficacious chemical inhibitors of agr signaling can be developed that promote host defense against SSTIs while sparing the normal microbiota of the skin is unknown. In a high throughput screen, we identified a small molecule inhibitor (SMI), savirin (S. aureus virulence inhibitor) that disrupted agr-mediated quorum sensing in this pathogen but not in the important skin commensal Staphylococcus epidermidis. Mechanistic studies employing electrophoretic mobility shift assays and a novel AgrA activation reporter strain revealed the transcriptional regulator AgrA as the target of inhibition within the pathogen, preventing virulence gene upregulation. Consistent with its minimal impact on exponential phase growth, including skin microbiota members, savirin did not provoke stress responses or membrane dysfunction induced by conventional antibiotics as determined by transcriptional profiling and membrane potential and integrity studies. Importantly, savirin was efficacious in two murine skin infection models, abating tissue injury and selectively promoting clearance of agr+ but not Δagr bacteria when administered at the time of infection or delayed until maximal abscess development. The mechanism of enhanced host defense involved in part enhanced intracellular killing of agr+ but not Δagr in macrophages and by low pH. Notably, resistance or tolerance to savirin inhibition of agr was not observed after multiple passages either in vivo or in vitro where under the same conditions resistance to growth inhibition was induced after passage with conventional antibiotics. Therefore, chemical inhibitors can selectively target AgrA in S. aureus to promote host defense while sparing agr signaling in S. epidermidis and limiting resistance development.

A series of novel phenylamino quinazolinone derivatives were designed and synthesized as potential tyrosinase inhibitors. Among these compounds, 9r emerged as the most potent derivative, exhibiting IC 50 values of 17.02 ± 1.66 µM, compared to kojic acid as the positive control with an IC 50 value of 27.56 ± 1.27 µM. Antioxidant assessment of 9r compounds showed 24.67% inhibition at 100 µM. Molecular docking studies of these derivatives were conducted, revealing their proper fitting within the enzyme’s active site. Additionally, density functional theory analysis was performed on the potent derivatives, indicating their stability and reactivity. Notably, the highest values of the energy gap were observed in 9r and 9s derivatives, underscoring their potential efficacy. Further kinetic studies of compound 9r , identified as the most potent derivative, demonstrated a competitive mode of inhibition with a K i value of 14.87 µM. Molecular dynamics simulations of the 9r -tyrosinase complex revealed stability over time, with a reduction in critical residual fluctuation during the simulation. Overall, these findings contribute to a deeper understanding of the potential therapeutic value of these derivatives as tyrosinase inhibitors.

The pathogenesis of chronic obstructive pulmonary disease (COPD) remains unclear, but involves loss of alveolar surface area (emphysema) and airway inflammation (bronchitis) as the consequence of cigarette smoke (CS) exposure. Previously, we demonstrated that autophagy proteins promote lung epithelial cell death, airway dysfunction, and emphysema in response to CS; however, the underlying mechanisms have yet to be elucidated. Here, using cultured pulmonary epithelial cells and murine models, we demonstrated that CS causes mitochondrial dysfunction that is associated with a reduction of mitochondrial membrane potential. CS induced mitophagy, the autophagy-dependent elimination of mitochondria, through stabilization of the mitophagy regulator PINK1. CS caused cell death, which was reduced by administration of necrosis or necroptosis inhibitors. Genetic deficiency of PINK1 and the mitochondrial division/mitophagy inhibitor Mdivi-1 protected against CS-induced cell death and mitochondrial dysfunction in vitro and reduced the phosphorylation of MLKL, a substrate for RIP3 in the necroptosis pathway. Moreover, Pink1(-/-) mice were protected against mitochondrial dysfunction, airspace enlargement, and mucociliary clearance (MCC) disruption during CS exposure. Mdivi-1 treatment also ameliorated CS-induced MCC disruption in CS-exposed mice. In human COPD, lung epithelial cells displayed increased expression of PINK1 and RIP3. These findings implicate mitophagy-dependent necroptosis in lung emphysematous changes in response to CS exposure, suggesting that this pathway is a therapeutic target for COPD.