1496552-50-1Relevant articles and documents
Development and Implementation of an Aluminum-Promoted Phosphorylation in the Uprifosbuvir Manufacturing Route
Liu, Zhuqing,Klapars, Artis,Simmons, Bryon,Bellomo, Ana,Kalinin, Alexei,Weisel, Mark,Hill, Jerry,Silverman, Steven M.
, p. 661 - 667 (2020/12/21)
A novel application of the synthesis of pronucleotide (ProTide) 5′-phosphoramidate monoesters promoted by aluminum-based Lewis acids is described. In the multikilogram synthesis of uprifosbuvir (MK-3682, 1), a clinical candidate for the treatment of hepatitis C, this methodology provided >100:1 diastereoselectivity at the phosphorus stereocenter and >100:1 selectivity for the 5′-mono phosphorylation over undesired bisphosphorylation side products. The high diastereoselectivity and mono/bis ratio achieved enabled elimination of the tedious workup associated with the tert-butyl magnesium chloride protocol commonly used to install this functionality in similar nucleotide prodrugs, achieving a near doubling of the isolated yield from 45% to 81%. The process development and purity control strategy of MK-3682, as well as handling of the pyrophoric reagent on scale, will also be discussed.
Synthesis and Anti-HCV Activities of 4′-Fluoro-2′-Substituted Uridine Triphosphates and Nucleotide Prodrugs: Discovery of 4′-Fluoro-2′- C-methyluridine 5′-Phosphoramidate Prodrug (AL-335) for the Treatment of Hepatitis C Infection
Wang, Guangyi,Dyatkina, Natalia,Prhavc, Marija,Williams, Caroline,Serebryany, Vladimir,Hu, Yujian,Huang, Yongfei,Wan, Jinqiao,Wu, Xiangyang,Deval, Jerome,Fung, Amy,Jin, Zhinan,Tan, Hua,Shaw, Kenneth,Kang, Hyunsoon,Zhang, Qingling,Tam, Yuen,Stoycheva, Antitsa,Jekle, Andreas,Smith, David B.,Beigelman, Leonid
, p. 4555 - 4570 (2019/05/17)
We report the synthesis and biological evaluation of a series of 4′-fluoro-2′-C-substituted uridines. Triphosphates of the uridine analogues exhibited a potent inhibition of hepatitis C virus (HCV) NS5B polymerase with IC50 values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrugs of these uridine analogues demonstrated a very potent activity with EC50 values as low as 20 nM. A lead compound AL-335 (53) demonstrated high levels of the nucleoside triphosphate in vitro in primary human hepatocytes and Huh-7 cells as well as in dog liver following a single oral dose. Compound 53 was selected for the clinical development where it showed promising results in phase 1 and 2 trials.
The discovery of IDX21437: Design, synthesis and antiviral evaluation of 2′-α-chloro-2′-β-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors
Alexandre, Fran?ois-René,Badaroux, Eric,Bilello, John P.,Bot, Stéphanie,Bouisset, Tony,Brandt, Guillaume,Cappelle, Sylvie,Chapron, Christopher,Chaves, Dominique,Convard, Thierry,Counor, Clément,Da Costa, Daniel,Dukhan, David,Gay, Marion,Gosselin, Gilles,Griffon, Jean-Fran?ois,Gupta, Kusum,Hernandez-Santiago, Brenda,La Colla, Massimiliano,Lioure, Marie-Pierre,Milhau, Julien,Paparin, Jean-Laurent,Peyronnet, Jér?me,Parsy, Christophe,Pierra Rouvière, Claire,Rahali, Houcine,Rahali, Rachid,Salanson, Aurélien,Seifer, Maria,Serra, Ilaria,Standring, David,Surleraux, Dominique,Dousson, Cyril B.
, p. 4323 - 4330 (2017/09/12)
Herein we describe the discovery of IDX21437 35b, a novel RP D-aminoacid-based phosphoramidate prodrug of 2′-α-chloro-2′-β-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.
