Discovery of Ledipasvir (GS-5885): A Potent, Once-Daily Oral NS5A Inhibitor for the Treatment of Hepatitis C Virus Infection

Abstract

A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.

In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir

“…Several direct-acting antiviral (DAA) agents have been approved to treat patients with HCV, including the nucleotide analog NS5B polymerase inhibitor sofosbuvir (Sovaldi; SOF) and the NS5A inhibitor ledipasvir (LDV) (3)(4)(5).…”

Simultaneous determination of the brand new two-drug combination for the treatment of hepatitis C: Sofosbuvir/ledipasvir using smart spectrophotometric methods manipulating ratio spectra

“…It can be used in combination with other pharmaceuticals for the treatment of HCV infections [3]. Ledipasvir (LDP) is an HCV NS5A inhibitor and has an antiviral activity against HCV (genotypes 1a and 1b) [4] that was approved by the US Food and Drug Administration (FDA) as a fixed-dose two drug combination with SFB in 2014 for the treatment of HCV chronic infection of genotype 1 [5].…”

Matched and mixed cap derivatives in the tetracyclic indole class of HCV NS5A inhibitors

“…7 To date, four NS5A inhibitors have gained regulatory approval and are shown in Figure 1. [8][9][10][11] A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.…”

“…Approved HCV NS5A inhibitors. [8][9][10][11] In a continued effort to explore the tetracyclic indole class of NS5A inhibitors, efforts were undertaken to examine the impact of structural modifications of the two imidazole L-Pro-L-Val methyl carbamate (Moc) regions (Figure 1). While a brief SAR exploration had been previously conducted in an earlier series (MK-4882) to replace the two terminal L-valine methyl carbamate moieties (Val Moc), 11 we sought to explore the impact on the virologic profile of broader changes to the amino acid end caps in the current series.…”