14 research outputs found
Benzyl Acetate and Benzyl Ether Groups as Latent Initiator Sites for Atom Transfer Radical Polymerization
No full textBenzyl Acetate and Benzyl Ether Groups as
Latent Initiator Sites for Atom Transfer
Radical Polymerizatio
The Synthesis of 2‐Ketopiperazine Acetic Esters and Amides from Ethylenediamines with Maleates and Maleimides.
No full textNovel, potent and orally bioavailable indolizidinone-derived inhibitors of the hepatitis C virus NS3 protease
No full textDiscovery of GS-9256: A novel phosphinic acid derived inhibitor of the hepatitis C virus NS3/4A protease with potent clinical activity
No full textNovel, potent, and orally bioavailable phosphinic acid inhibitors of the hepatitis C virus NS3 protease
No full text
Optimization of Pharmacokinetics through Manipulation of Physicochemical Properties in a Series of HCV Inhibitors
No full textNature
No full textThe most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14\u2009h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10\u2009mg\u2009kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.R01 AI113321/AI/NIAID NIH HHS/United StatesR01AI113321/AI/NIAID NIH HHS/United States2017-08-10T00:00:00Z26934220PMC5551389719
Discovery of a 2′-fluoro-2′- C -methyl C -nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties
No full textDiscovery of the First <i>C</i>‑Nucleoside HCV Polymerase Inhibitor (GS-6620) with Demonstrated Antiviral Response in HCV Infected Patients
No full textHepatitis C virus (HCV) infection
presents an unmet medical need requiring more effective treatment
options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have
demonstrated pan-genotypic activity and durable antiviral response
in the clinic, and they are likely to become a key component of future
treatment regimens. NI candidates that have entered clinical development
thus far have all been N-nucleoside derivatives.
Herein, we report the discovery of a C-nucleoside
class of NS5B inhibitors. Exploration of adenosine analogs in this
class identified 1′-cyano-2′-C-methyl
4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of
NS5B. A monophosphate prodrug approach afforded a series of compounds
showing submicromolar activity in HCV replicon assays. Further pharmacokinetic
optimization for sufficient oral absorption and liver triphosphate
loading led to identification of a clinical development candidate
GS-6620. In a phase I clinical study, the potential for potent activity
was demonstrated but with high intra- and interpatient pharmacokinetic
and pharmacodynamic variability
