220592-65-4

Upstream product

• 770-12-7 O-phenyl phosphorodichloridate 
• 75-84-3 2,2-dimethyl-propanol-1 
• 104-15-4 toluene-4-sulfonic acid 
• 125511-59-3 (S)-neopentyl 2-((tert-butoxycarbonyl)amino)propanoate 

Downstream Products

• 1613590-37-6 C₄₇H₅₄FN₆O₁₀P 
• 1613591-82-4 C₂₇H₃₇F₂N₆O₈P 
• 1615696-45-1 (2S)-neopentyl 2-(((((2R,3R,4S,5R)-5-(2-amino-6-ethoxy-1H-purin-9(6H)-yl)-3-fluoro-4-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate 
• 1255860-35-5 C₂₅H₃₄N₃O₁₀P 
• 1430067-56-3 2-deoxy-2,2-difluoro-β-D-arabinofuranose (P_R)-1-O-phenyl-(neopentoxy-alaninyl)phosphate 
• 1430067-57-4 2-deoxy-2,2-difluoro-β-D-arabinofuranose (P_S)-1-O-phenyl-(neopentoxy-alaninyl)phosphate 
• 1430067-58-5 2-deoxy-2,2-difluoro-α-D-arabinofuranose (P_R)-1-O-phenyl-(neopentoxy-alaninyl)phosphate 
• 1430067-59-6 2-deoxy-2,2-difluoro-α-D-arabinofuranose (P_S)-1-O-phenyl-(neopentoxy-alaninyl)phosphate 
• 1443987-51-6 C₃₅H₄₀F₂NO₁₂P 
• 1430067-90-5 2-deoxy-2-fluoro-α-D-arabinofuranose (P_R)-1-O-phenyl-(neopentoxy-alaninyl)phosphate 
• 1430067-91-6 2-deoxy-2-fluoro-α-D-arabinofuranose (P_S)-1-O-phenyl-(neopentoxy-alaninyl)phosphate 

Relevant academic research and scientific papers

Nucleotide prodrugs of 2′-deoxy-2′-spirooxetane ribonucleosides as novel inhibitors of the HCV NS5B polymerase

The limited efficacy, in particular against the genotype 1 virus, as well as the variety of side effects associated with the current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs of 2′-deoxy-2′-spirooxetane ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 μM, measured in the Huh7-replicon cell line, with no apparent cytotoxicity (CC50 > 98.4 μM). Confirming recent findings, the 2′-spirooxetane moiety was identified as a novel structural motif in the field of anti-HCV nucleosides. A convenient synthesis was developed that enabled the synthesis of a broad set of nucleotide prodrugs with varying substitution patterns. Extensive formation of the triphosphate metabolite was observed in both rat and human hepatocyte cultures. In addition, after oral dosing of several phosphoramidate derivatives of compound 21 to rats, substantial hepatic levels of the active triphosphate metabolite were found.

Application of ProTide technology to gemcitabine: A successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development

Gemcitabine is a nucleoside analogue commonly used in cancer therapy but with limited efficacy due to a high susceptibility to cancer cell resistance. The addition of a phosphoramidate motif to the gemcitabine can protect it against many of the key cancer resistance mechanisms. We have synthesized a series of gemcitabine phosphoramidate prodrugs and screened for cytostatic activity in a range of different tumor cell lines. Among the synthesized compounds, one in particular (NUC-1031, 6f) was shown to be potent in vitro. Importantly, compared with gemcitabine, 6f activation was significantly less dependent on deoxycytidine kinase and on nucleoside transporters, and it was resistant to cytidine deaminase-mediated degradation. Moreover, 6f showed a significant reduction in tumor volumes in vivo in pancreatic cancer xenografts. The ProTide 6f is now in clinical development with encouraging efficacy signals in a Phase I/II study, which strongly supports the ProTide approach to generate promising new anticancer agents.

PHOSPHORAMIDATE DERIVATIVES OF GUANOSINE NUCLEOSIDE COMPOUNDS FOR TREATMENT OF VIRAL INFECTIONS

Phosphoramidate compounds derived from guanine bases having enhanced therapeutic potency are provided, and these compounds in particular have enhanced potency with respect to treatment of viral infections, such as hepatitis C virus. Pharmaceutical compositions, methods of preparing the compounds, and methods of using the compounds and compositions to treat viral infections are also provided.

Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives

We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.