China
Africa
Explore chapters and articles related to this topic
Transformin Growth Factor-β
Published in Jason Kelley, Cytokines of the Lung, 2022
A novel approach to the determination of the specific TGF-β subtypes involved in vivo has been pioneered by Potts and colleagues (1991). They focused on the role of TGF-β in driving progenitor cardiac cells of the heart valves and membranous septum to undergo epithelial-mesenchymal transformation. A phosphoramidate-modified oligonucleotide complementary to TGF-β3 mRNA was capable of inhibiting this process. Oligonucleotides to TGF-β1, TGF-β2, and TGF-β4 were not. Hence, only TGF-β3 can be implicated in this critical developmental step. This approach obviously has considerable potential for future application in other organs and disease models.
Prevention of Restenosis by Gene Targeting
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Michael J. Mann, Victor J. Dzau, Heiko E. von der Leyen
Although traditional phosphodiester ODN are susceptible to exonuclease and endonuclease digestion, ODN with phosphodiesterase-resistant modifications of the phosphate backbone, such as phosphoramidate and phosphorothioate ODN, can be used for more prolonged inhibition of gene expression (Wickstrom, 1991; Crooke, 1993).
Hepatitis C Virus and Its Inhibitors
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Phosphoramidate prodrugs typically involve masking the phosphate with an α-amino acid ester and an aryloxy group (Mehellou et al. 2009). An IC50 of 0.13 μM of the triphosphate in an RdRp assay and favorable pharmacokinetic properties in rats made 2′-C-methylguanosine (6) an interesting candidate to test this prodrug approach. Extensive SAR studies on a series of 5′-phosphoramidate derivatives of 2′-C-methylguanosine (14, Figure 3.10) (McGuigan et al. 2009, 2010a) culminated in the synthesis of the 2′-C-methyl-6-methoxyguanosine phosphoramidate INX-08189 (BMS-986094, 15), a double prodrug of 2′-C-methylguanosine, which was readily converted to the active 5′-triphosphate in primary human hepatocytes and in the liver of rats after oral dosing (Vernachio et al. 2011). Anti-HCV activity of 15 in a GT1 replicon assay was 10 nM (Table 3.3), a 350-fold improvement compared to the EC50 of the parent 2′-C-methylguanosine, of which about a factor six is attributable to the 6-O-methyl group. A variety of substituents in the 6-position of the purine improved potency against HCV compared to guanosine, most likely by increasing the compounds’ lipophilicity, thus improving cellular uptake (McGuigan et al. 2011b). The synthesis of phosphoramidate prodrugs resulted in a mixture of diastereomers with the phosphorus atom as an additional chiral center. The individual diastereomers of 15 showed similar EC50s; consequently, a mixture of isomers was advanced into clinical development (McGuigan et al. 2010b). INX-08189 completed a phase 1b dose-finding study in individuals infected with GT1 HCV. The median HCV RNA reduction after seven days of monotherapy was 4.25 log10 IU/mL at the highest dose of 200 mg qd (Table 3.4). The synergy between 15 and RBV observed in vitro could be confirmed in the clinic: Viral load reduction after seven days of treatment with 100 mg INX-08189 qd plus RBV was 3.79 log10 IU/mL compared to 2.54 log10 IU/mL for monotherapy with the same dose (Table 3.4) (Rodriguez-Torres et al. 2011). In a subsequent phase 2 study, patients infected with GT 2/3 HCV were dosed with 25 mg, 50 mg, or 100 mg of BMS-986094 qd, or with placebo, respectively, combined with IFN and RBV for 12 weeks, followed by response-guided treatment with IFN and RBV for another 12 weeks. The eRVR rates ranged from 71% to 78% in the groups treated with triple combination therapy compared to 58% in the placebo control group (Lawitz et al. 2012a). Further development of BMS-986094 was terminated due to severe cardiovascular adverse events during a phase 2 study (Bristol-Myers Squibb Company 2012).
An overview of ProTide technology and its implications to drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Michaela Serpi, Fabrizio Pertusati
Usually, the phosphorylating agents are used as a pair of diastereoisomers at the phosphorus center. This leads to the formation of two diastereoisomeric aryloxyphosphoramidates in a 1:1 ratio RP and SP. Such mixtures are very difficult to separate by standard chromatographic methods, or by crystallization. Considerable efforts were then directed to the development of diastereoselective strategies toward phosphoramidates. The demand for efficient diastereoselective methods raised after the discovery of a significant difference in the antiviral activity between SP and RP isomers of clinical candidates [26–28]. The superior activity observed with one isomer was proved to correlate with its ability to produce higher level of the triphosphate species compared to the other [28]. Evidence that the two phosphoramidates (and phosphonamidates) diastereoisomers can be processed at different rates in enzymatic assay by carboxypeptidase were also reported [20,29,30].
Antisense Oligonucleotide Therapy for Ophthalmic Conditions
Published in Seminars in Ophthalmology, 2021
Kevin Ferenchak, Iris Deitch, Rachel Huckfeldt
The phosphodiester backbone of single-stranded RNA and AON can easily degrade in a cell, which limited the practical applications of antisense therapy for many years. Since they were first described, modifications have developed, which make AON viable in vivo with a longer half-life, more resistant to degradation, and more likely to be taken up by cells. These modifications include changes such as the first generation phosphorothioate (PS) backbone, which improved nuclear uptake.23 A phosphoramidate morpholino has been investigated to improve stability, but its viability may be limited by quicker clearance.24,25 Common second generation modifications are a 2ʹO-methoxy ethyl (2MOE) or 2ʹO-methyl (2OME) group attached to the sugar residues of the PS backbone, which further increase stability and cellular uptake.26,27
In silico docking studies and synthesis of new phosphoramidate derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole as potential antimicrobial agents
Published in Journal of Receptors and Signal Transduction, 2020
Munichandra Reddy Sivala, Venkataramaiah Chintha, Krishna Murthy Potla, Sampath Chinnam, Naga Raju Chamarthi
In conclusion, a series of new phosphoramidate derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole were synthesized in good to excellent yields (78–96%). 4b, 4d, 4h, 4i, and 4j compounds exhibited potent anti-bacterial and fungal activity against all the test pathogens when compared to the standards. All the other compounds have exhibited moderate activity against both the bacterial and fungal strains. Molecular docking studies disclosed that the synthesized compounds have exhibited noteworthy binding modes with high dock scores ranging from −7.2 to −9.5 against 3V2B protein when compared with the standard drugs norfloxacin (−5.8) and nystatin (−6.6). To our knowledge, this is the first report concerning the synthesis and bioactive profiles of new phosphoramidate containing 6-fluoro-3-(piperidin-4-yl)benzo[d] isoxazole scaffolds. Therefore, the current study will open new vistas for the discovery of new and highly potent pharmacologically active phosphoramidates which will have applications in medicinal, synthetic and organophosphorus chemistry.