To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2011.08.034 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
An attempted oxidative coupling approach to the scholarinine A framework.
Tetrahedron Lett
March 2024
Department of Chemistry, University of California, Berkeley, CA 94720, United States.
In this manuscript, an oxidative carbon-carbon bond forming reaction to construct the framework of alkaloids such as scholarinine A is explored using a constrained substrate. Instead of the desired carbon-carbon bond formation between an indole C3 position and a malonate group, a competing carbon-nitrogen bond between the malonate and indole C3 position was observed to form. This work adds to the growing body of substrates for oxidative carbon-carbon bond formation and importantly, demonstrates that these reactions are challenging for some conformationally constrained substrates.
View Article and Find Full Text PDFCrosslinking intermodular condensation in non-ribosomal peptide biosynthesis.
Nature
December 2024
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA.
Non-ribosomal peptide synthetases are assembly line biosynthetic pathways that are used to produce critical therapeutic drugs and are typically arranged as large multi-domain proteins called megasynthetases. They synthesize polypeptides using peptidyl carrier proteins that shuttle each amino acid through modular loading, modification and elongation steps, and remain challenging to structurally characterize, owing in part to the inherent dynamics of their multi-domain and multi-modular architectures. Here we have developed site-selective crosslinking probes to conformationally constrain and resolve the interactions between carrier proteins and their partner enzymatic domains.
View Article and Find Full Text PDFStructural Insights into Helix-Loop-Helix Peptides for "Ligand-Targeting" Intracellular Drug Delivery via VEGF Receptor-Mediated Endocytosis.
Biochem Biophys Res Commun
December 2024
Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka, 599-8531, Japan. Electronic address:
Article Synopsis
- Researchers developed "ligand-targeting" peptide-drug conjugates (PDCs) using a specific helix-loop-helix peptide (M49) that targets human VEGF to deliver drugs.
- The biochemical studies showed that the M49 peptide forms a complex with VEGF, which then interacts with cell surface receptors to trigger the cell's uptake process.
- An X-ray crystal structure of the M49/VEGF complex revealed details about the binding mechanism and target specificity, providing insights for future drug design and development.
Conformation matters: siRNAs with antisense strands with 5'-()-vinyl-phosphonate-α-L-LNA elicit stronger RNAi-mediated gene silencing than those with 5'-()-vinyl-phosphonate-LNA.
Chem Commun (Camb)
November 2024
Alnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
Conformationally constrained nucleotides, LNA or α-L-LNA, at the 5' terminus of the antisense strand impeded gene silencing of small interfering RNA (siRNA) by hindering phosphorylation, thereby deterring loading into the RNA-induced silencing complex. Installation of a phosphate mimic, ()-vinyl phosphonate (VP), improved activity considerably. Gene silencing was more efficient when the antisense strand of the siRNA was modified with 5'-VP-α-L-LNA, which adopts a C3'- (south) conformation, than when the antisense strand was modified with 5'-VP-LNA, which adopts a C3'- (north) pucker.
View Article and Find Full Text PDFConformationally Constrained Isoquinolinones as Orally Efficacious Hepatitis B Capsid Assembly Modulators.
ACS Med Chem Lett
September 2024
Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States.
Isoquinolinone-based HBV capsid assembly modulators that bind at the dimer:dimer interface of HBV core protein have been shown to suppress viral replication in chronic hepatitis B patients. Analysis of their binding mode by protein X-ray crystallography has identified a region of the small molecule where the application of a constraint can lock the preferred binding conformation and has allowed for further optimization of this class of compounds. Key analogues demonstrated single digit nM EC values in reducing HBV DNA in a HepDE19 cellular assay in addition to favorable ADME and pharmacokinetic properties, leading to a high degree of oral efficacy in a relevant hydrodynamic injection mouse model of HBV infection, with effecting a 3 log decline in serum HBV DNA levels at a once daily dose of 1 mg/kg.
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!