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The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC50 = 86 nM in macrophages as the clinical candidate. Structure activity relationships established that the 1'-CN group and C-linked nucleobase were critical for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of 4b to enable preclinical efficacy in a non-human-primate EBOV challenge model. Once-daily 10 mg/kg iv treatment on days 3-14 postinfection had a significant effect on viremia and mortality, resulting in 100% survival of infected treated animals [Nature 2016, 531, 381-385]. A phase 2 study (PREVAIL IV) is currently enrolling and will evaluate the effect of 4b on viral shedding from sanctuary sites in EBOV survivors. [ABSTRACT FROM AUTHOR]

The reaction of substituted ethylenediamines with various fumarates, maleates, and maleimides to form substituted ketopiperazine acetic acid esters and amides was investigated. This method affords a straightforward, high yield approach to a variety of potential peptidomimetics and can yield surprising results with regard to regio- and stereoselectivity. [Copyright &y& Elsevier]

A series of 2′-fluorinated C -nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2′-fluoro-2′- C -methyl adenosine C -nucleoside ( 15 ) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant ( 53 ) with favorable pharmacokinetic properties including efficient liver delivery in animals. [ABSTRACT FROM AUTHOR]

Novel 4′-substituted β- d -2′-deoxy-2′-α-fluoro (2′d2′F) nucleoside inhibitors of respiratory syncytial virus (RSV) are reported. The introduction of 4′-substitution onto 2′d2′F nucleoside analogs resulted in compounds demonstrating potent cell based RSV inhibition, improved inhibition of the RSV polymerase by the nucleoside triphosphate metabolites, and enhanced selectivity over incorporation by mitochondrial RNA and DNA polymerases. Selectivity over the mitochondrial polymerases was found to be extremely sensitive to the specific 4′-substitution and not readily predictable. Combining the most potent and selective 4′-groups from N -nucleoside analogs onto a 2′d2′F C -nucleoside analog resulted in the identification of β- d -2′-deoxy-2′-α-fluoro-4′-α-cyano-5-aza-7,9-dideaza adenosine as a promising nucleoside lead for RSV. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infectionpresents an unmet medical need requiring more effective treatmentoptions. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) havedemonstrated pan-genotypic activity and durable antiviral responsein the clinic, and they are likely to become a key component of futuretreatment regimens. NI candidates that have entered clinical developmentthus far have all been N-nucleoside derivatives.Herein, we report the discovery of a C-nucleosideclass of NS5B inhibitors. Exploration of adenosine analogs in thisclass identified 1′-cyano-2′-C-methyl4-aza-7,9-dideaza adenosine as a potent and selective inhibitor ofNS5B. A monophosphate prodrug approach afforded a series of compoundsshowing submicromolar activity in HCV replicon assays. Further pharmacokineticoptimization for sufficient oral absorption and liver triphosphateloading led to identification of a clinical development candidateGS-6620. In a phase I clinical study, the potential for potent activitywas demonstrated but with high intra- and interpatient pharmacokineticand pharmacodynamic variability. [ABSTRACT FROM AUTHOR]

Investigationof thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guidedby measurement of cell culture medium binding, revealed the structure–activityrelationships for intrinsic cellular potency. The pharmacokineticprofile was enhanced through incorporation of heterocyclic etherson the N-alkyl substituent. Hydroxyl groups wereincorporated to modulate protein binding. Intrinsic potency was furtherimproved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2clinical candidate GS-9669. The unexpected activity of this compoundagainst the clinically relevant NS5B M423T mutant, relative to thewild type, was shown to arise from both the N-alkylsubstituent and the N-acyl group. [ABSTRACT FROM AUTHOR]

Abstract: The discovery of GS-9451 is reported. Modification of the P3 cap and P2 quinoline with a series of solubilizing groups led to the identification of potent HCV NS3 protease inhibitors with greatly improved pharmacokinetic properties in rats, dogs and monkeys. [Copyright &y& Elsevier]

Abstract: A novel, potent, and orally bioavailable class of product-like inhibitors of the HCV NS3 protease was discovered by constraining the P2–P3 amide bond and the P3 hydrocarbon substituent to the protease-bound conformation. This preorganization was accomplished by incorporation of the P2–P3 amide into a six-membered ring attached to the P2-proline 5-position. Isothermal calorimetric characterization of the role of hydrocarbon substitution of this six-membered ring, upon binding the HCV NS3 protease, was found to be exclusively entropic in nature. The synthesis, preliminary SAR and pharmacokinetic profiling of this compact, indolizidinone-derived scaffold are described. [Copyright &y& Elsevier]

Abstract: A potent and novel class of product-like inhibitors of the HCV NS3 protease was discovered by employing a phosphinic acid as a carboxylate isostere. The replicon activity and pharmacokinetic profile of this series of compounds was optimized by exploring the substitution of the phosphinic acid, as well as conformationally constraining these compounds through macrocyclization. The syntheses and preliminary biological evaluation of these phosphinic acids is described. [Copyright &y& Elsevier]

Abstract: A novel class of phosphonate derivatives was designed to mimic the interaction of product-like carboxylate based inhibitors of HCV NS3 protease. A phosphonic acid (compound 2) was demonstrated to be a potent HCV NS3 protease inhibitor, and a potential candidate for treating HCV infection. The syntheses and preliminary biological evaluation of this phosphonate class of inhibitor are described. [Copyright &y& Elsevier]

Abstract: A potent and novel class of phosphinic acid derived product-like inhibitors of the HCV NS3/4A protease was discovered previously. Modification of the phosphinic acid and quinoline heterocycle led to GS-9256 with potent cell-based activity and favorable pharmacokinetic parameters. Based on these attributes, GS-9256 was advanced to human clinical trial as a treatment for chronic infection with genotype 1 HCV. [Copyright &y& Elsevier]