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Improving non-specific binding and solubility: bicycloalkyl groups and cubanes as para-phenyl bioisosteres
No full textBicycloalkyl groups have previously been described as phenyl group bioisosteres. This article describes the synthesis of new building blocks allowing their introduction in complex molecules, and explores their use as a means to modify the physicochemical properties of drug candidates and improve the quality of imaging agents. In particular, the replacement of an aromatic ring with a bicyclo[1.1.1]pentane-1,3-diyl (BCP) group improves solubility by at least 50-fold, and markedly decreases non-specific binding (NSB) as measured using CHI(IAM), the chromatographic hydrophobicity index on immobilized artificial membranes. Structural variations with the bicyclo[2.2.2]octane-1,4-diyl group led to more lipophilic molecules and did not show the same benefits with regard to non-specific binding or solubility, whereas substitutions with cubane-1,4-diyl also showed an improvement in both parameters. These results confirm the potential advantages of both BCP and cubane groups as bioisosteric replacements for optimizing para-phenyl substituted molecules
Medicinal Chemists Don’t Just Make Drugs – the Art of Developing Low Molecular Weight Imaging Agents in Switzerland
No full textRadiolabeled molecular imaging agents are useful to study drug distribution, target engagement and disease progression in human patients. Medicinal chemists often develop them in parallel to drug discovery programs, to facilitate clinical development or to better understand physiological and pathological processes. While the properties required for imaging agents differ from those of drug candidates, their optimization follows similar principles. Developing them for clinical use also requires a multidisciplinary approach, and is best conducted in a close partnership between pharmaceutical and academic research centers. This article reviews recent scientific advances towards the identification and development of low molecular weight imaging agents in Switzerland
Improving paediatric asthma care in Zambia
No full textProblem: In 2008, the prevalence of paediatric asthma in Zambia was unknown and the
national treatment guideline was outdated.
Approach: We created an international partnership between Zambian clinicians, the
Zambian Government and a pharmaceutical company to address shortcomings in
asthma treatment. We did two studies, one to estimate prevalence in the capital of
Lusaka and one to assess attitudes and practices of patients. Based on the information
obtained, we educated health workers and the public. The information from the studies
was also used to modernize government policy for paediatric asthma management.
Local setting: The health care system in Zambia is primarily focused on acute care
delivery with a focus on infectious diseases. Comprehensive services for
noncommunicable diseases are lacking. Asthma management relies on treatment of
acute exacerbations instead of disease control.
Relevant changes: Seven percent of children surveyed had asthma (255/3911). Of the
120 patients interviewed, most (82, 68%) used oral short-acting β-agonists for symptom
control; almost half (59, 49%) did not think the symptoms were preventable and 43%
(52/120) thought inhalers were addictive. These misconceptions informed broad-based
educational programmes. We used a train-the-trainer model to educate health care
workers and ran public awareness campaigns. Access to inhalers was increased and
Zambian standard treatment guideline for paediatric asthma was revised to include
steroid inhalers as control treatment.
Lessons learnt: Joint activities were required to change paediatric asthma care in
Zambia. Success will depend on local sustainability, and it may be necessary to shift
resources to mirror the disease burden
Toward the Chemoenzymatic Synthesis of DNA-Encoded Libraries
No full textDNA-encoded libraries (DELs) have become a powerful platform in drug discovery, practiced both by the pharmaceutical industry and academia. Each small molecule contained in a DEL is covalently linked to a DNA tag which serves as an amplifiable barcode facilitating binder identification. However, the chemical diversity accessible in DELs remains limited by the need to perform reactions under conditions that preserve the integrity of the DNA tag. Additionally, chemical reactions must proceed with high efficiency and selectivity to minimize side products and unreacted starting materials, which cannot be removed and may hamper hit identification. Consequently, expanding the DEL chemical space requires the development of methods that combine high reaction performance with DNA compatibility. In this outlook, we highlight the potential of enzymatic catalysis for on-DNA synthesis, which offers a promising route to expand DEL-accessible chemical space
Evaluation of food effects on two anticancer drugs in humans: Application of physiologically based pharmacokinetic modeling as a surrogate strategy to minimize In-Vivo studies in drug development
No full textPurpose
In oral drug delivery system, food may influence the effectiveness of the drug by modulating its bioavailability. Understanding these interactions between food and drugs is crucial during drug development. However, the conventional approaches used to identify them are expensive and time-consuming clinical trials, which are often impractical. The objective of this study is to address these challenges by leveraging physiologically based pharmacokinetic(PBPK) models as efficient in-silico tools to predict food effects using significantly less time and resources.
Methods
This work focused on developing and validating PBPK models of two low solubility anticancer drugs, Alectinib and Acalabrutinib, utilizing minimal in-vitro characterization data available at the early stage of drug development to demonstrate successful prediction of food effect. The models were developed for healthy humans incorporating drug-specific physicochemical properties, in-vitro characterization data, and physiological parameters of the gastrointestinal tract under both fasted and fed conditions.
Results
The prediction accuracy of the developed models was validated against the observed clinical data and further used for virtual population simulation to predict the food effect. The model validation parameters met the 2-fold error limit criteria. The predicted food effect data revealed that, despite low solubility, Alectinib exhibited a significant positive food effect, while Acalabrutinib showed no clinically relevant impact, consistent with the observed clinical data.
Conclusion
This work underscores the significance of the in-silico modeling and simulation approach in predicting the food effect of orally administered drugs, which could be used to minimize or optimize time-extensive and cost-expensive clinical trials in drug development
Pharmacogenomic, pharmacokinetic, and safety analysis of CYP3A4/CYP3A5 polymorphisms of midostaurin in patients with acute myeloid leukemia.
No full textAbstract
Purpose
Midostaurin is predominantly metabolized by cytochrome P450 (CYP) 3A4 to form two active metabolites, CGP62221 and CGP52421. The current analysis from UNIFY, a randomized, double-blind, phase 3 study, investigated the impact of genetic polymorphism of CYP3A4/CYP3A5 on the exposure of midostaurin and its active metabolites, and on treatment-related toxicity in patients with FLT3-mutation-negative acute myeloid leukemia (AML).
Methods
Based on the literature, CYP3A4/CYP3A5 polymorphic variants were selected and further interpreted as individual, combined, and clustered phenotypes. The pharmacokinetic (PK) parameters for midostaurin and the active metabolites were estimated based on concentration data collected after the first dose (full PK profile) and during the induction, consolidation, and post-consolidation phases at trough (pre-dose) and post-dose 3 h. Adverse event (AE) summaries included all treatment-emergent AEs starting on or after study day 1 and starting no later than 30 days after study treatment discontinuation.
Results
PK profiles and parameters of midostaurin and its metabolites after the first dose and multiple dosing, at steady state, at the different visits through different phases of the study were generally comparable across CYP3A4/CYP3A5 polymorphic variants and clustered phenotypes. The safety profile of midostaurin in this study was consistent with the known safety profile of midostaurin in FLT3-mutation-positive patients with AML. No meaningful differences were observed in the safety profile of midostaurin versus placebo in patients with CYP3A4/CYP3A5 polymorphic variants and clustered phenotype groups.
Conclusion
Our extensive pharmacogenomic/PK/safety analysis in patients with AML does not indicate the need for dose adjustments of midostaurin based on CYP3A4/CYP3A5 polymorphic variants
Discovery of IID432: A Highly Efficacious and Safe Cyanotriazole Inhibitor of Trypanosoma cruzi Topoisomerase II for Short-Duration Curative Treatment of Chagas Disease
No full textChagas Disease is a neglected tropical disease caused by the parasite Trypanosoma cruzi affecting millions worldwide. Current therapy suffers from variable efficacy, longer treatment duration and undesirable safety profile. There is an urgent need for more effective, safer, and shorter-duration treatments. A phenotypic screen of the Novartis compound library against the bloodstream form of the closely related Trypanosoma brucei parasite identified a series of cyanotriazole (CT) compounds with rapid sterilizing activity across kinetoplastid parasites by specifically inhibiting parasite topoisomerase II. Initial CT compounds suffered from safety liabilities such as lymphopenia and neutrophilia due to modulation of the sphingolipid pathway. Subsequent medicinal chemistry optimization of the first-generation CTs led to the development of a tailored aminopyrrolidine core structure for Chagas Disease, enhancing ADME properties and mitigating sphingolipid pathway modulation. IID432 demonstrated potent activity against T. cruzi (EC50 = 8 nM) and achieved relapse-free cure in a mouse model of chronic Chagas Disease with a shorter treatment duration. These findings suggest that IID432 has the potential to serve as a fast and curative treatment for Chagas Disease
Lymphotoxin-dependent elevated meningeal CXCL13:BAFF ratios drive gray matter injury.
No full textIn multiple sclerosis (MS), B cell-rich tertiary lymphoid tissues (TLTs) in the brain leptomeninges associate with cortical gray matter injury. Using a model of Th17 cell-driven experimental autoimmune encephalomyelitis in mice, we found that inhibitors of Bruton's tyrosine kinase (BTKi) prevented TLT formation and cortical pathology in a B cell activating factor (BAFF)-dependent manner. BTKi reduced expression of lymphotoxin ligands, and cotreatment with a lymphotoxin-β receptor agonist abrogated the benefits of BTKi. TLT and cortical pathology tracked with a high CXCL13:BAFF ratio in the leptomeninges, which was reduced by BTKi. Moreover, we observed high CXCL13:BAFF ratios in post mortem cerebral spinal fluid from patients with MS and pathologically confirmed leptomeningeal inflammation, as well as in living patients with MS and radiologically confirmed paramagnetic rim lesions. In summary, using experimental autoimmune encephalomyelitis, we revealed a molecular circuit that leads to TLT formation and cortical injury with translational relevance for detection of this pathology in patients with MS
Designing integrated early-phase protocols to reduce substantial modifications, including considerations for patient cohorts – a multi-stakeholder consensus view for a practical approach in Germany
No full text• Frequent substantial modifications for initiating new trial parts slow down development and reduce transparency.
• Combining healthy volunteers and patients in a single early-phase trial raises safety, feasibility, and regulatory concerns.
• A multi-stakeholder consensus in Germany identified regulatory pathways to enable seamless transitions within integrated protocols for non-ATMP (advanced therapy medicinal product), non-oncology trials.
• The EMA FIH (first-in-human) guideline supports predefined transitions if scope, safety thresholds, and decision rules are clearly described.
• The German guardrail concept clarifies when transitions do not require a substantial modification, enhancing planning certainty.
• Actionable recommendations are provided on protocol design, decision criteria, and governance structures to enable early inclusion of patients without compromising safety or compliance.
• First positive experience has been gained with the presented framework in Germany
Biomimetic oral drug delivery: Translating nature's design into therapeutic innovation.
No full textOral drug delivery, the most patient friendly administration route offers convenience and compliance but faces formidable biological barriers. Enzymatic degradation, mucosal entrapment, efflux transport and extensive first-pass metabolism drastically reduce the effectiveness of sensitive therapeutics including peptides, proteins, nucleic acids and vaccines. Conventional formulations often fail to overcome these challenges highlighting the need for innovative approaches. Biomimetic drug delivery has emerged as a transformative strategy. By emulating structures and functions from cells, membranes, exosomes, viruses and gut microbiota these systems achieve immune evasion, mucus penetration, site-specific targeting and stimulus-responsive release. Such approaches improve formulation stability and in vivo absorption but also promise precise and patient centric therapies. This review provides a comprehensive overview of biomimetic oral systems highlighting their mechanisms, design principles and translational potential. Recent advances include cell membrane-coated nanoparticles for tumor targeting and immune modulation, exosome-inspired carriers for protein and RNA transport, virus-like particles (VLPs) for oral vaccines, and mucoadhesive or mucus-penetrating polymers modeled on pathogen strategies. Complementary pH, enzyme and redox-responsive platforms exploit gastrointestinal (GI) microenvironments to ensure controlled release. Emerging tools such as bioinspired computational modeling, 3D/4D printing, organoid-on-chip models and CRISPR/Cas-based platforms accelerate optimization and clinical translation. Although most technologies remain in preclinical development, early findings demonstrate superior pharmacokinetics, therapeutic efficacy, and safety over conventional systems. This article critically examines biomimetic oral drug delivery addressing advances and underlying mechanisms including regulatory considerations and future directions. They stand poised to form the foundation of next-generation precision therapeutics