Non-nucleoside Inhibitors of the Measles Virus RNA-Dependent RNA Polymerase: Synthesis, Structure–Activity Relationships, and Pharmacokinetics

Abstract

The measles virus (MeV), a member of the paramyxovirus family, is an important cause of pediatric morbidity and mortality worldwide. In an effort to provide therapeutic treatments for improved measles management, we previously identified a small, non-nucleoside organic inhibitor of the viral RNA-dependent RNA polymerase (RdRp) by means of high-throughput screening (HTS). Subsequent structure-activity relationship (SAR) studies around the corresponding pyrazole carboxamide scaffold led to the discovery of 2 (AS-136a), a first generation lead with low nanomolar potency against life MeV and attractive physical properties suitable for development. However, its poor water solubility and low oral bioavailability (F) in the rat suggested that the lead could benefit from further SAR studies to improve the biophysical characteristics of the compound. Optimization of in vitro potency and aqueous solubility led to the discovery of 2o (ERDRP-00519), a potent inhibitor of MeV (EC50 = 60 nM) with aqueous solubility of approximately 60 μg/ml. The agent shows a 10-fold exposure (AUC/Cmax) increase in the rat model relative to 2, displays near dose proportionality in the range of 10 mg/kg to 50 mg/kg, and exhibits good oral bioavailability (F = 39%) in the rat. The significant solubility increase appears linked to the improved oral bioavailability.

An Orally Available, Small-Molecule Polymerase Inhibitor Shows Efficacy Against a Lethal Morbillivirus Infection in a Large Animal Model

“…The resulting lead ERDRP-0519 (fig. 1A) showed an excellent 39% oral availability in the rat model, high bidirectional membrane permeability (26), and was suitable for synthesis scale-up (fig. S1).…”

Fatal Measles Virus Infection Prevented by Brain-Penetrant Fusion Inhibitors

“…(http:// www.who.int/immunization_monitoring/diseases/measles _monthlydata/en/). Specific antiviral therapies are urgently needed to complement vaccination and achieve the global elimination of measles (4,52,53). MV therapeutics could be used for the rapid control of local outbreaks, protection of immunocompromised people and infants prior to vaccination, and improved management of acute and persistent disease (54)(55)(56)(57).…”

Development of an allosteric inhibitor class blocking RNA elongation by the respiratory syncytial virus polymerase complex

“…In our experience, ligand-driven QSARs show good predictive power for second-stage optimization, provided they are informed by meaningful training and test sets (27,(45)(46)(47). Particularly detrimental to model accuracy are data sets representing overlapping, but distinct, SARs, such as antiviral activity due to specific target binding and cytotoxic effects.…”