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Author Notes:

Corresponding author: Phone: 404-712-8680; asun2@emory.edu

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Research Funding:

This work was supported, in part, by Public Health Service Grants AI071002 and AI085328 (to R. K. P.) from the NIH/NIAID and by Public Health Service Grant HG003918-02 (to J.P.S.) from the NIH.

Keywords:

  • measles virus
  • RNA-dependent RNA polymerase activity inhibitor
  • AS-136a
  • ERDRP-00519
  • pharmacokinetics

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

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Journal Title:

Journal of Medicinal Chemistry

Volume:

Volume 55, Number 9

Publisher:

, Pages 4220-4230

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2012 American Chemical Society

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