Favorable Pharmacokinetic Profile Research Articles

Integrated virtual screening and MD simulation study to discover potential inhibitors of mycobacterial electron transfer flavoprotein oxidoreductase.

Tuberculosis (TB) continues to be a major global health burden, with high incidence and mortality rates, compounded by the emergence and spread of drug-resistant strains. The limitations of current TB medications and the urgent need for new drugs targeting drug-resistant strains, particularly multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, underscore the pressing demand for innovative anti-TB drugs that can shorten treatment duration. This has led to a focus on targeting energy metabolism of Mycobacterium tuberculosis (Mtb) as a promising approach for drug discovery. This study focused on repurposing drugs against the crucial mycobacterial protein, electron transfer flavoprotein oxidoreductase (EtfD), integral to utilizing fatty acids and cholesterol as a carbon source during infection. The research adopted an integrative approach, starting with virtual screening of approved drugs from the ZINC20 database against EtfD, followed by molecular docking, and concluding with molecular dynamics (MD) simulations. Diacerein, levonadifloxacin, and gatifloxacin were identified as promising candidates for repurposing against TB based on their strong binding affinity, stability, and interactions with EtfD. ADMET analysis and anti-TB sensitivity predictions assessed their pharmacokinetic and therapeutic potential. Diacerein and levonadifloxacin, previously unexplored in anti-tuberculous therapy, along with gatifloxacin, known for its efficacy in drug-resistant TB, have broad-spectrum antimicrobial properties and favorable pharmacokinetic profiles, suggesting potential as alternatives to current TB treatments, especially against resistant strains. This study underscores the efficacy of computational drug repurposing, highlighting bacterial energy metabolism and lipid catabolism as fruitful targets. Further research is necessary to validate the clinical suitability and efficacy of diacerein, levonadifloxacin, and gatifloxacin, potentially enhancing the arsenal against global TB.

Safety, tolerability and pharmacokinetics of subcutaneous meropenem as an alternative to intravenous administration.

Subcutaneous delivery of antibiotics is a practical alternative to IV administration. Meropenem is commonly used to treat infections caused by resistant Gram-negative organisms. This was a prospective, crossover self-controlled study in 11 stable inpatients established on meropenem. Participants received a single dose of subcutaneous meropenem, in 50 mL normal saline via gravity feed. Venous blood sampling was performed at baseline, 0.5, 1, 2, 4 and 8 h following the subcutaneous and IV doses. Antibiotic concentrations were measured using UPLC-MS/MS. Pharmacokinetic data were analysed using a non-linear mixed-effects modelling approach. Pain scores and infusion site reactions (oedema/erythema) were assessed. Subcutaneous meropenem was well tolerated. The bioavailability of subcutaneous administration was 81.5% (95% CI 71.6%-93.2%). Increasing BMI was associated with slower absorption from subcutaneous tissue. Compared with IV, subcutaneous administration resulted in lower peak and higher trough concentrations. Despite the lower bioavailability observed, the PTA for free drug concentrations greater than the MIC for more than 40% of the time between doses was higher for subcutaneous than IV administration at MIC values between 0.03 and 8 mg/L. Simulated subcutaneous doses of 1.5 g twice daily, or 3 g continuous 24 h infusion had improved PTA relative to standard IV dosing of 1 g three times daily. Subcutaneous meropenem appears to be well tolerated and has a favourable pharmacokinetic profile. Either 1.5 g twice daily or 3 g as a 24 h subcutaneous infusion could be considered for future evaluation.

Exploring phytochemical inhibitors of protein kinase C alpha for therapeutic targeting of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by neurodegeneration linked to amyloid-β (Aβ) plaques and tau protein tangles. Protein kinase C alpha (PKCα) plays a crucial role in modulating amyloid-β protein precursor (AβPP) processing, potentially mitigating AD progression. Consequently, PKCα stands out as a promising target for AD therapy. Despite the identification of numerous inhibitors, the pursuit of more effective and precisely targeted PKCα inhibitors remains crucial. In this study, we employed an integrated virtual screening approach of molecular docking and molecular dynamics (MD) simulations to identify phytochemical inhibitors of PKCα from the IMPPAT database. Molecular docking screening via InstaDock identified compounds with strong binding affinities to PKCα. Subsequent ADMET and PASS analyses filtered out compounds with favorable pharmacokinetic profiles. Interaction analysis using Discovery Studio Visualizer and PyMOL further elucidated binding conformations of selected compounds with PKCα. Top hits underwent 200 ns MD simulations using GROMACS to validate stability of the interactions. Finally, we propose two phytochemicals, Kammogenin and Imperialine, with appreciable drug-likeliness and binding potential with PKCα. Taken together, the findings suggest Kammogenin and Imperialine as potential PKCα inhibitors, highlighting their therapeutic promise for AD after further validation.

Amphetamine Derivatives as Potent Central Nervous System Multitarget SERT/NET/H3 Agents: Synthesis and Biological Evaluation

In this research, a variety of novel amphetamine derivatives were synthesized and assessed for their potential as multifaceted antidepressant agents. Among these compounds, compound 11b demonstrated potent inhibitory effects on both serotonin and noradrenaline transporters (SERT/NET) and high affinity for histamine H3 receptor (H3R), and displayed low affinity for off-target receptors (H1, α1) and hERG channels, which can reduce the prolongation of the QT interval. Molecular docking studies offered a rational binding model of compound 11b when it forms a complex with SERT, NET, and the histamine H3 receptor. In vivo behavioral studies, compound 11b dose-dependently reduced the immobility duration in the mouse FST and TST assays without a stimulatory effect on the locomotor activity. Furthermore, compound 11b had a favorable pharmacokinetic profile in rats. Thus, compound 11b has the potential to develop a novel class of drugs for the treatment of depression.

Revolutionizing new drug discovery: Harnessing AI and machine learning to overcome traditional challenges and accelerate targeted therapies

Designing highly targeted, selective drugs with desirable absorption, distribution, metabolism, excretion, and pharmacokinetic (PK) profiles; single-digit nanomolar efficacy; and a wider therapeutic index are challenging. In the traditional drug discovery process, researchers screen thousands of chemical compounds during pre-clinical development, progressing through hit identification, lead optimization, and candidate selection to shortlist – potential clinical candidates with favorable PK profiles, high tolerability, and manageable toxicity. The selected candidate must demonstrate sufficient efficacy in treating the target disease in humans. Despite these efforts, the success rate of the pre-clinical candidate to sail through Phase I, Phase II, and Phase III in clinical trials remains exceedingly low. Supported by powerful data-driven tools, artificial intelligence (AI) has transformed this traditional drug discovery process by enabling the analysis of large quantities of omics, phenotypic, and expression data to identify the biological mechanisms of pathological conditions and in turn identify druggable proteins or genes. The generative AI-powered toolbox creates novel compounds from scratch, assists scientists in optimizing druggability attributes, and bridges the differences between animal and human physiology and anatomy to predict potential toxicity in humans with high accuracy. This review discusses the bottlenecks in the traditional drug discovery approach, the impact of AI and machine learning (ML) in drug discovery, and potential challenges associated with AI/ML adoption.

Identification of Oral Bioavailable Coumarin Derivatives as Potential AR Antagonists Targeting Prostate Cancer.

Androgen receptor (AR) is a crucial driver of prostate cancer (PCa), but acquired resistance to AR antagonists significantly undermines their clinical efficacy. We previously discovered coumarin derivative 1, which is capable of disrupting AR ligand-binding domain dimers, offering the potential for overcoming resistance. However, its poor oral bioavailability limited further development. In this study, comprehensive structure optimizations led to compound 4a (IC50 = 0.051 μM), which exhibited comparable AR antagonistic activity to enzalutamide (IC50 = 0.060 μM) and demonstrated excellent selectivity over other nuclear receptors in vitro. Especially, 4a showed superior efficacy against ARF876L/T877A and ARW741C mutants compared to darolutamide and enzalutamide. Moreover, 4a exhibited favorable pharmacokinetic profiles (F = 66.24%) in vivo and significant tumor growth inhibition in an LNCaP xenograft mouse model upon oral administration. These results highlight the potential of 4a as a promising oral AR antagonist for overcoming drug resistance in PCa.

Recent Advancements in Benzothiazinones (BTZ) Analogs as DprE1 Inhibitor for Potent Antitubercular Therapeutics

AbstractBenzothiazinone analogs have emerged as a promising class of compounds having potent antimycobacterial activity, particularly against Mycobacterium tuberculosis, the pathogen responsible for tuberculosis. This review highlights the development of benzothiazinone analogs as potential antitubercular agents from the beginning to the recent advancement in the past decade. These compounds have shown potent activity, including drug‐resistant strains of Mycobacterium tuberculosis. Structure–activity relationship studies and modifications have improved their efficacy. Benzothiazinone analogs have favorable pharmacokinetic profiles and show promise in preclinical studies. Challenges include addressing resistance mechanisms and ensuring safety. Their unique mode of action and promising properties make them attractive candidates for the battle against drug‐resistant tuberculosis.

Synthesis, Molecular Docking, and Biological Evaluation of Novel Indole-triazole Conjugates.

Indole-triazole conjugates have emerged as promising candidates for new drug development. Their distinctive structural characteristics, coupled with a wide array of biological activities, render them a captivating and promising field of research for the creation of novel pharmaceutical agents. This study aimed to synthesize indole-triazole conjugates to investigate the influence of various substituents on the functional characteristics of indole-triazole hybrids. It also aimed to study the binding modes of new hybrids with the DNA Gyrase using molecular docking studies. A new set of indole-triazole hybrids was synthesized and characterized using various physicochemical and spectral analyses. All hybrids underwent in-silico pharmacokinetic prediction studies. The antimicrobial efficacy of the hybrids was assessed using tube dilution and agar diffusion methods. Additionally, the in-vitro antioxidant activity of synthesized compounds was determined using the 1,1-diphenyl-2-picryl-hydrazyl free radical scavenging assay. Furthermore, in silico molecular docking studies were performed to enhance our comprehension of how the synthesized compounds interact at the molecular level with DNA gyrase. Pharmacokinetic predictions of synthesized hybrids indicated favourable pharmacokinetic profiles, and none of the compounds violated the Lipinski rule of five. Notably, compound 6, featuring a cyclohexanol substituent, demonstrated superior antimicrobial and antioxidant activity (EC50 value = 14.23 μmol). Molecular docking studies further supported the in vitro antioxidant and antimicrobial findings, revealing that all compounds adeptly fit into the binding pocket of DNA Gyrase and engaged in interactions with crucial amino acid residues. In summary, our research underscores the efficacy of molecular hybridization in shaping the physicochemical, pharmacokinetic, and biological characteristics of novel indole-triazole derivatives.

Structure–Activity Relationship Studies of Imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine Derivatives to Develop Selective FGFR Inhibitors as Anticancer Agents for FGF19-overexpressed Hepatocellular Carcinoma

The aberrant activation of fibroblast growth factor (FGF) and FGF receptor (FGFR)-mediated signaling pathways are associated with cancer development, including hepatocellular carcinoma (HCC). A novel series of imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine, containing an acrylamide covalent warhead, were synthesized as selective FGFR 1-4 inhibitors. Compound 7n was identified as the most potent inhibitor against FGFR1, 2, and 4, with IC50 values of 8/4 nM (FGFR1/2) and 3.8 nM (FGFR4), and the covalent docking analyses suggested that 7n form a covalent adduct with cysteine residue on the hinge or p-loop of FGFR. Compound 7n exhibited a favorable pharmacokinetic profile and significant in vivo antitumor efficacy in human liver cancer xenograft mouse models (xenograft, FGF/FGFR-dependent HCC cells).

Virtual screening and lead optimization of Desmostachya bipinnata-derived FGFR inhibitors for oral squamous cell carcinoma management

BackgroundOral cancer remains a major global health challenge with limited therapeutic options, highlighting the need for novel treatments. Phytochemicals derived from Desmostachya bipinnata (Db), a plant used in traditional Chinese medicine for its anti-inflammatory and analgesic properties, have demonstrated potential anti-cancer effects. However, their mechanisms of action, particularly in targeting Fibroblast Growth Factor Receptor (FGFR) in oral cancer, are not well characterized. ObjectiveThis study aimed to leverage in-silico drug design methodologies to identify bioactive compounds from Db with potential FGFR-inhibiting activity for the treatment of oral cancer. MethodologyAn MTT assay was conducted using KB cell lines to evaluate cytotoxic effects, while thirty-eight phytochemicals from Db were screened through in silico approaches for their pharmacokinetics, toxicity, and drug-likeness. Molecular docking studies were performed to assess binding affinities to the FGFR protein. The biological activity and toxicity of the compounds were predicted to prioritize candidates for further investigation. ResultsFourteen compounds were identified as promising candidates based on their drug-like properties, favourable pharmacokinetic profiles, significant FGFR binding affinities, and predicted anti-cancer activity. These compounds also demonstrated potential for oral bioavailability and central nervous system penetration, supporting their candidacy for further drug development. Notably, the traditional use of Desmostachya bipinnata in TCM emphasizes its role in enhancing overall vitality and immune function, which may synergize with the identified FGFR-inhibiting properties in the context of oral cancer treatment ConclusionThe phytochemicals from Desmostachya bipinnata exhibit significant potential as FGFR-targeted therapeutic agents for oral cancer. Further experimental validation and optimization of these lead compounds could contribute to the development of novel, effective treatments for oral cancer and related conditions

Bempedoic Acid, the First-in-Class Oral ATP Citrate Lyase Inhibitor with Hypocholesterolemic Activity: Clinical Pharmacology and Drug–Drug Interactions

Bempedoic acid is a new drug that improves the control of cholesterol levels, either as monotherapy or in combination with existing lipid-lowering therapies, and shows clinical efficacy in cardiovascular disease patients. Thus, patients with comorbidities and under multiple therapies may be eligible for bempedoic acid, thus facing the potential problem of drug–drug interactions (DDIs). Bempedoic acid is a prodrug administered orally at a fixed daily dose of 180 mg. The dicarboxylic acid is enzymatically activated by conjugation with coenzyme A (CoA) to form the pharmacologically active thioester (bempedoic acid–CoA). This process is catalyzed by very-long-chain acyl-CoA synthetase 1 (ACSVL1), expressed almost exclusively at the hepatic level. Bempedoic acid–CoA is a potent and selective inhibitor of ATP citrate lyase (ACL), a key enzyme in the biosynthetic pathway of cholesterol and fatty acids. The drug reduces low-density lipoprotein–cholesterol (LDL-C) (20–25%), non-high-density lipoprotein–cholesterol (HDL-C) (19%), apolipoprotein B (apoB) (15%), and total cholesterol (16%) in patients with hypercholesterolemia or mixed dyslipidemia. The drug has a favorable pharmacokinetics profile. Bempedoic acid and its metabolites are not substrates or inhibitors/inducers of cytochrome P450 (CYP450) involved in drug metabolism. On the other hand, bempedoic acid–glucuronide is a substrate for organic anion transporter 3 (OAT3). Bempedoic acid and its glucuronide are weak inhibitors of the OAT2, OAT3, and organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Thus, bempedoic acid could inhibit (perpetrator) the hepatic uptake of OATP1B1/3 substrate drugs and the renal elimination of OAT2 and OAT3 substrates and could suffer (victim) the effect of OAT3 transporter inhibitors, reducing its renal elimination. Based on these pharmacological characteristics, here, we describe the potential DDIs of bempedoic acid with concomitant medications and the possible clinical implications.

Synthesis, biological evaluation, molecular docking analyses, and ADMET study of azo derivatives containing 1-naphthol against MβL-producing S. maltophilia

Stenotrophomonas maltophilia is a model organism exhibiting intrinsic antibiotic resistance, primarily due to its production of Mβ-lactamase enzymes that inactivate β-lactam antibiotics. This study aims to synthesize an azo derivative containing an oxazepine ring as a potential inhibitor of Mβ-lactamase. The molecular docking results revealed that the binding energies of the Mβ-lactamases ranged from − 5.95 to − 6.09 kcal/mol, indicating favourable interactions with the synthesized compounds. Two compounds were prepared: the first via aldol condensation of (A1) with p-hydroxybenzaldehyde to form (K1) and the second through Azo-Schiff base formation from 3,5-dimethylaniline, resulting in (L2) and (L18). Characterization of these compounds was conducted via FT-IR, CHN, 1H NMR, and 13C NMR spectroscopy. Antimicrobial activity was assessed through minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) tests, which yielded values ranging from 1.19 ± 1 to 0.02 µg/mL and from 1.12 ± 1 to > 0.04 µg/mL, respectively. Notably, the MBC/MIC ratios indicated that L2 and L18 exhibited significant bactericidal activity. In silico analysis via MOE 2015 software allowed us to determine the binding poses and energies of the synthesized inhibitors against Mβ-lactamase (PDB ID: 6UAF). The most stable conformation from the docking results was selected for further evaluation. Compared with standard ceftazidime, the synthesized compounds significantly inhibited Mβ-lactamase activity. Additionally, ADMET analysis indicated favourable pharmacokinetic profiles and low toxicity, suggesting promising oral drug-like properties for the synthesized molecules.

Discovery of Novel 5-(Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione Derivatives as Potent and Orally Bioavailable Inhibitors Targeting Ecto-5'-nucleotidase.

Ecto-5-nucleotidase (CD73) is overexpressed in a variety of cancers and associated with the immunosuppressive tumor microenvironment, making it an attractive target for cancer immunotherapy. Herein, we designed and synthesized a series of novel (pyridazine-3-yl)pyrimidine-2,4(1H,3H)-dione derivatives as CD73 inhibitors. These compounds exhibited remarkable inhibitory activity against CD73 in both enzymatic biochemical and cellular assays. Among them, compound 35j proved to be one of the most potent inhibitors and an uncompetitive inhibitor with no obvious cytotoxicity. This compound showed high metabolic stability in rat liver microsomes and favorable pharmacokinetic profiles in rats (T1/2 = 3.37 h, F = 50.24%). Importantly, orally administered 35j significantly inhibited tumor growth in the triple-negative breast cancer 4T1 mouse model (TGI = 73.6%, 50 mg/kg). Immunoassays suggested that 35j remarkably increased the infiltration of positive immune cells, thereby reinvigorating antitumor immunity. These results demonstrate that 35j is a potent CD73 inhibitor worthy of further development.

Pharmacokinetics of intramuscular L-carvone in sheep.

To measure and model concentrations of the analgesic L-carvone, a natural component of spearmint, over time when administered IM to sheep and to characterize L-carvone's effects on CBCs and clinical biochemistry panels. L-carvone formulated as a 50% solution (v/v) in ethanol and propylene glycol was administered at 71.6 mg/kg IM, split between each semitendinosus muscle in 6 sheep. Venous blood was sampled over 24 hours, and plasma was separated by centrifugation. Additional blood was collected for CBC and serum biochemical analysis, and tissues were sampled after euthanasia. L-carvone concentrations in plasma and tissue homogenates were measured using HPLC-MS-MS. Plasma pharmacokinetic data were described using a nonlinear mixed effects model. Complete blood count and biochemistry data were compared to baseline values using repeated-measures ANOVA and Holm-Šidák tests (P < .05). Maximum plasma concentrations ranged from 0.28 to 1.93 µg/mL and occurred within 9 to 15 minutes after injection. Pharmacokinetics were best described using 2 compartments. Elimination half-life was 33.7 minutes and 390.2 minutes in the central and peripheral compartments, respectively. Mild increases in neutrophil count and significant increases in creatinine kinase and aspartate aminotransferase were associated with injection site myonecrosis. No physical examination, behavioral, or other clinically significant laboratory changes were noted. Intramuscular L-carvone exhibits rapid time to peak concentration, relatively slow plasma elimination, and low tissue concentrations after 24 hours. L-carvone exhibits a favorable pharmacokinetic profile for an analgesic drug. A new L-carvone formulation or administration route is needed to reduce inflammation and necrosis at the injection site.

Spesolimab, the first-in-class anti-IL-36R antibody: From bench to clinic.

Inflammatory diseases that are driven by several pro-inflammatory cytokines has resulted in in the development of targeted therapies across different disease settings. Interleukin (IL)-36 cytokines have been implicated in several inflammatory diseases. In this review we describe the scientific evidence surrounding the use of the IL-36 receptor (IL-36R)-targeting antibody, spesolimab, in IL-36-mediated skin diseases: generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), hidradenitis suppurativa, and Netherton syndrome (NS). Spesolimab, a high affinity, specific, humanized, antagonistic immunoglobulin G1 antibody, targets the IL-36R at a binding site distinct from its agonists, IL-36α/β/γ, and at least one endogenous antagonist, IL-36R antagonist. Invitro and invivo data for spesolimab show effective inhibition of IL-36R-mediated signaling pathways, and six Phase I studies in healthy volunteers presented a favorable safety and pharmacokinetic (PK) profile, leading to the development of a clinical trial program to evaluate spesolimab in the treatment of IL-36R-mediated diseases. Six studies (including an expanded access program) have evaluated the efficacy, safety, PKs, and pharmacogenomics of spesolimab in patients with GPP flares. Spesolimab treatment of GPP flares resulted in rapid and sustained improvements in pustular and skin clearance, and clinically significant improvements in patient-reported symptoms and quality of life. Spesolimab also significantly reduces the risk of GPP flares and flare occurrence, preventing disease worsening and has a favorable safety profile. There have been three trials of spesolimab in PPP; further evaluation is needed to better define those patients who might benefit from the treatment. A trial of spesolimab in NS is ongoing, while other spesolimab trials suggest that IL-36 may only play a secondary role in the pathogenesis of atopic dermatitis. In conclusion, research into spesolimab has provided much needed insight into the role of IL-36 in the human immune system and the mechanism behind IL-36-mediated inflammatory diseases. Spesolimab provides an efficacious targeted treatment for GPP, a disease with a high unmet medical need.

Design, synthesis and biological evaluation of arylpropylamine derivatives as potential multi-target antidepressants

In this study, a series of novel arylpropylamine derivatives were designed, synthesized and evaluated as potential multi-target antidepressants. Among them, compound (R)-13j displayed unique pharmacological features, exhibiting excellent inhibitory potency against serotonin and noradrenaline transporters (SERT/NET) and high affinity for 5-HT2A/2C receptor, and showing low affinity for histamine H1, adrenergic α1 receptors and hERG channels (to reduce QT interval prolongation). Molecular docking studies provided a rational binding model of (R)-13j in complex with SERT and 5-HT2A/2C receptor. In animal models, compound (R)-13j dose-dependently reduced the immobility time in the tail suspension test (TST) and the forced swimming test (FST) in mice, with higher efficacy when compared to duloxetine, and showed no stimulatory effect on the locomotor activity. Moreover, compound (R)-13j significantly shortened the immobility time in the ACTH-induced rat model of treatment-resistant depression (TRD). Furthermore, compound (R)-13j also exhibited a higher threshold for acute toxicity than duloxetine. In addition, compound (R)-13j possessed a favorable pharmacokinetic profile in mice. Taken together, compound (R)-13j may constitute a novel class of drugs for the treatment of depression.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose riliprubart, an anti-C1s humanized monoclonal antibody in East-Asian adults: results from a Phase 1, randomized, open-label trial

ABSTRACT Objectives This Phase 1 trial was planned to investigate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of a single dose of riliprubart in healthy East-Asian adult participants. Methods A single-center, parallel-group, randomized, open-label, single-dose study was performed to evaluate the PK, PD, safety, and tolerability of riliprubart (50 mg/kg intravenous [IV] or 600 mg subcutaneous [SC]) in 37 healthy East-Asian (Chinese, Japanese, and Korean) participants. Results Riliprubart was slowly absorbed after SC administration (median tmax: 7.01–10.48 days) and showed a long half-life after IV or SC administration (mean: 9.52–11.0 weeks), with a bioavailability of 74.6% after SC administration. The PD profiles, which are evaluated by classical complement pathway activity or CH50, were similar and largely overlapped across East-Asian participants after a single IV or SC dose. Riliprubart was safe and well tolerated in participants following a single IV or SC dose. Conclusions Riliprubart was safe and well tolerated and demonstrated favorable PK and PD profiles in healthy East-Asian participants following a single IV or SC dose. These results are comparable to first-in-human study results from non-East-Asian participants and support the same dosing regimen of riliprubart for global simultaneous clinical development. Clinical trial registration This trial is registered at https://cris.nih.go.kr (identifier: KCT0006571).

Novel 1,2,3-triazole derivatives containing benzoxazinone scaffold: Synthesis, docking study, DFT analysis and biological evaluation

In order to address the drastic demand for novel broad-spectrum antibacterial and anticancer medicines with enhanced activity, computer modelling was utilized to rationally develop newer anticancer triazole based drugs. A unique series of benzo[d][1,3]oxazin-4-one linked 1,2,3-triazoles was synthesised in five steps, with good yields and an assessment of their antibacterial and anticancer activities. IR spectroscopy, 1H NMR, 13C NMR, and mass spectrometry were used to characterize the synthesis of triazole compounds. From antibacterial screening, the prepared derivatives namely, 8a, 8e, 8h and 8k showed excellent inhibitory potential against S. aureus with ZI of 28 ± 0.48, 30 ± 0.42, 30 ± 0.11, 35 ± 0.23 mm respectively, compared to moxifloxacin (33 ± 0.15 mm). Compared to doxorubicin (IC50 = 2.45 ± 0.14 μM), compounds 8h and 8k demonstrated superior and exceptional cytotoxicity against the A549 cell line (IC50 = 2.30 ± 0.26 and 1.90 ± 0.30 μM, respectively). Latter All the derivatives were further subjected to in silico docking studies against human lung (PDB: 2P85), VEGFR2 kinase domain (PDB: 3CP9) and could serve as ideal leads for additional modification in the field of anticancer research. Based on docking results, 8e showed that the amino acids Arg373(A), Gly113(A), Glu103(A), Asp108(A), Ser119(A), Asn375(A), Val374(A), Lys387(A), and Asn120(A) exhibited highly stable binding to cytochrome P4502A13 receptor of lung cancer. Furthermore, Density Functional Theory (DFT) calculations are performed to support the molecular docking studies. Compounds 8e, 8h, and 8k were discovered to have estimated energy gaps (eV) of 3.181, 4.034, and 3.539 eV, respectively. Triazole 8h exhibited the lowest chemical hardness (1.962 eV) and the highest chemical softness (0.252 eV), which also suggests that it is more reactive than all the other compounds under study. Moreover, these scaffolds physicochemical characteristics, filtration molecular properties, assessment of toxicity, and bioactivity scores were assessed in relation to ADME (absorption, distribution, metabolism, and excretion). In conclusion, we discovered a novel benzoxazinone linked 1,2,3-triazoles with promising antimicrobial and anticancer activity and a favorable pharmacokinetic profile.

Structure-activity optimization of ryanodine receptor modulators for the treatment of catecholaminergic polymorphic ventricular tachycardia

BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia disorder associated with potentially lethal arrhythmias. Most CPVT cases are caused by inherited variants in the gene encoding ryanodine receptor type 2 (RYR2). ObjectiveThe goal of this study was to investigate the structure-activity relationship of tetracaine derivatives and to test a lead compound in a mouse model of CPVT. MethodsWe synthesized >200 tetracaine derivatives and characterized 11 of those. The effects of these compounds on Ca2+ handling in cardiomyocytes from R176Q/+ mice was tested with confocal microscopy. The effects of lead compound MSV1302 on arrhythmia inducibility and cardiac contractility were tested by programmed electrical stimulation and echocardiography, respectively. Plasma and microsomal stability and cytotoxicity assays were also performed. ResultsCa2+ imaging revealed that 4 of 11 compounds suppressed sarcoplasmic reticulum Ca2+ leak through mutant RyR2. Two compounds selected for further testing exhibited a half-maximal effective concentration of 146 nM (MSV1302) and 49 nM (MSV1406). Whereas neither compound altered baseline electrocardiogram intervals, only MSV1302 suppressed stress- and pacing-induced ventricular tachycardia in vivo in R176Q/+ mice. Echocardiography revealed that the lead compound MSV1302 did not negatively affect cardiac inotropy and chronotropy. Finally, compound MSV1302 did not block INa, ICa,L, or IKr; it exhibited excellent stability in plasma and microsomes, and it was not cytotoxic. ConclusionStructure-activity relationship studies of second-generation tetracaine derivatives identified lead compound MSV1302 with a favorable pharmacokinetic profile. MSV1302 normalized aberrant RyR2 activity in vitro and in vivo, without altering cardiac inotropy, chronotropy, or off-target effects on other ion channels. This compound may be a strong candidate for future clinical studies to determine its efficacy in CPVT patients.

Design, synthesis, and structure–activity relationships of xanthine derivatives as broad-spectrum inhibitors of coronavirus replication

Illuminated by insights into the hijacking of host cellular metabolism by coronaviruses, we identified an initial hit compound 7030B-C5, characterized by a xanthine scaffold, via a cellular-level phenotypic screening from a domestic repertoire of lipid-modulating agents. A series of derivatives were synthesized and optimized through comprehensive structure–activity relationship (SAR) studies focusing on the N-1, C-8, and N-7 positions of xanthine and preliminary exploration on the N-3 position and parent nucleus. Compounds 10e, 10f and 10o, featuring modifications at the N-7 position, showed inhibitory activity with half maximal effective concentration (EC50) values in the three-digit nanomolar range against human coronavirus-229Ehuman coronavirus-229E (HCoV-229E). In particular, compound 10o exerted superior potency across various coronavirus strains, including HCoV-229E, HCoV-OC43, and the Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Further investigations revealed that 10o acted on the post-entry stages of virus replication and exhibited a distinctive antiviral mechanism from that of clinically approved nirmatrelvir and molnupiravir. Moreover, drug combination study indicates that 10o operates additively with nirmatrelvir, molnupiravir or omicsynin B4, a dual inhibitor of host proteases for S protein priming. Additionally, in vivo assessments show that 10o has favorable pharmacokinetic and safety profiles compared to its parent compound 7030B-C5. These findings underscore the potential of 10o as a promising antiviral candidate for the treatment of current and potential future coronavirus infections.