A new series of pyrazolo[1,5-a]pyrimidines exemplified by compound 1, has been identified with moderate activity (IC50=165nM), following GSK256066 rescaffolding. Compound 1 optimization at positions 2, 3, 6 and 7 gave compound 10 with high in vitro activity (IC50=0.7nM). Modeling studies based on the PDB structure 3GWT with compound 5 showed the expected overlay with the carboxamide, the aryl moiety and the sulfone. Cyclisation of the primary amide to the 5 position of the pyrazolo[1,5-a]pyrimidines scaffold afforded compounds 15 and 16 with 200-fold enhancement in activity and cellular potency.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2015.11.093 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Electrochemical Synthesis of Polyaniline@Nano Zinc Oxide/Modified Multiwalled Carbon Nanotubes Nanocomposite Coating for Solid Phase Microextraction of Some Polycyclic Aromatic Hydrocarbons in Coffee and Grilled Meat.
J Sep Sci
January 2025
Herbal and Traditional Medicines Research Center, Kerman University of Medical Sciences, Kerman, Iran.
Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic compounds resulting from incomplete burning of organic materials. This work describes the successful layer-by-layer fabrication of a novel zinc oxide nanocomposite made of zinc oxide nanoparticles, aniline, sodium dodecyl sulfate, and modified multi-walled carbon nanotubes on a stainless steel wire by electrodeposition. The coating and extraction conditions were screened, optimized, and validated using factorial design and central composite design, respectively.
View Article and Find Full Text PDFBetacoronaviruses Differentially Activate the Integrated Stress Response to Optimize Viral Replication in Lung-Derived Cell Lines.
Viruses
January 2025
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
The betacoronavirus genus contains five of the seven human coronaviruses, making it a particularly critical area of research to prepare for future viral emergence. We utilized three human betacoronaviruses, one from each subgenus-HCoV-OC43 (embecovirus), SARS-CoV-2 (sarbecovirus), and MERS-CoV (merbecovirus)-, to study betacoronavirus interactions with the PKR-like ER kinase (PERK) pathway of the integrated stress response (ISR)/unfolded protein response (UPR). The PERK pathway becomes activated by an abundance of unfolded proteins within the endoplasmic reticulum (ER), leading to phosphorylation of eIF2α and translational attenuation.
View Article and Find Full Text PDFSpermine Significantly Increases the Transfection Efficiency of Cationic Polymeric Gene Vectors.
Pharmaceutics
January 2025
School of Pharmacy, Changzhou University, Changzhou 213164, China.
Non-viral vectors have gained recognition for their ability to enhance the safety of gene delivery processes. Among these, polyethyleneimine (PEI) stands out as the most widely utilized cationic polymer due to its accessibility. Traditional methods of modifying PEI, such as ligand conjugation, chemical derivatization, and cross-linking, are associated with intricate preparation procedures, limited transfection efficiency, and suboptimal biocompatibility.
View Article and Find Full Text PDFDevelopment of Novel Fluticasone/Salmeterol/Tiotropium-Loaded Dry Powder Inhaler and Bioequivalence Assessment to Commercial Products in Rats.
Pharmaceutics
January 2025
College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea.
/: Inhaler devices have been developed for the effective delivery of inhaled medications used in the treatment of pulmonary diseases. However, differing operating procedures across the devices can lead to user errors and reduce treatment efficacy, especially when patients use multiple devices simultaneously. To address this, we developed a novel dry powder inhaler (DPI), combining fluticasone propionate (FP), salmeterol xinafoate (SX), and tiotropium bromide (TB) into a single device designed for bioequivalent delivery compared to existing commercial products in an animal model.
View Article and Find Full Text PDFAdvances in Pure Drug Self-Assembled Nanosystems: A Novel Strategy for Combined Cancer Therapy.
Pharmaceutics
January 2025
Nanjing Medical Center for Clinical Pharmacy, Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
Nanoparticle-based drug delivery systems hold great promise for improving the effectiveness of anti-tumor therapies. However, their clinical translation remains hindered by several significant challenges, including intricate preparation processes, limited drug loading capacity, and concerns regarding potential toxicity. In this context, pure drug-assembled nanosystems (PDANSs) have emerged as a promising alternative, attracting extensive research interest due to their simple preparation methods, high drug loading efficiency, and suitability for large-scale industrial production.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!