Optimization of potent and selective quinazolinediones

Inhibitors of respiratory syncytial virus that block RNA-dependent RNA-polymerase complex activity

Daljit S. Matharu, Daniel P. Flaherty, Denise S. Simpson, Chad E. Schroeder, Donghoon Chung, Dan Yan, James W. Noah, Colleen Jonsson, E. Lucile White, Jeffrey Aubé, Richard K. Plemper, William E. Severson, Jennifer E. Golden

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

A quinazolinedione-derived screening hit 2 was discovered with cellular antiviral activity against respiratory syncytial virus (CPE EC50 = 2.1 μM), moderate efficacy in reducing viral progeny (4.2 log at 10 μM), and marginal cytotoxic liability (selectivity index, SI ∼ 24). Scaffold optimization delivered analogs with improved potency and selectivity profiles. Most notable were compounds 15 and 19 (EC50 = 300-500 nM, CC50 > 50 μM, SI > 100), which significantly reduced viral titer (>400,000-fold), and several analogs were shown to block the activity of the RNA-dependent RNA-polymerase complex of RSV.

Original languageEnglish (US)
Pages (from-to)10314-10328
Number of pages15
JournalJournal of Medicinal Chemistry
Volume57
Issue number24
DOIs
StatePublished - Dec 26 2014

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Quinazolinones
RNA Replicase
Respiratory Syncytial Viruses
Antiviral Agents

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Optimization of potent and selective quinazolinediones : Inhibitors of respiratory syncytial virus that block RNA-dependent RNA-polymerase complex activity. / Matharu, Daljit S.; Flaherty, Daniel P.; Simpson, Denise S.; Schroeder, Chad E.; Chung, Donghoon; Yan, Dan; Noah, James W.; Jonsson, Colleen; White, E. Lucile; Aubé, Jeffrey; Plemper, Richard K.; Severson, William E.; Golden, Jennifer E.

In: Journal of Medicinal Chemistry, Vol. 57, No. 24, 26.12.2014, p. 10314-10328.

Research output: Contribution to journalArticle

Matharu, DS, Flaherty, DP, Simpson, DS, Schroeder, CE, Chung, D, Yan, D, Noah, JW, Jonsson, C, White, EL, Aubé, J, Plemper, RK, Severson, WE & Golden, JE 2014, 'Optimization of potent and selective quinazolinediones: Inhibitors of respiratory syncytial virus that block RNA-dependent RNA-polymerase complex activity', Journal of Medicinal Chemistry, vol. 57, no. 24, pp. 10314-10328. https://doi.org/10.1021/jm500902x
Matharu, Daljit S. ; Flaherty, Daniel P. ; Simpson, Denise S. ; Schroeder, Chad E. ; Chung, Donghoon ; Yan, Dan ; Noah, James W. ; Jonsson, Colleen ; White, E. Lucile ; Aubé, Jeffrey ; Plemper, Richard K. ; Severson, William E. ; Golden, Jennifer E. / Optimization of potent and selective quinazolinediones : Inhibitors of respiratory syncytial virus that block RNA-dependent RNA-polymerase complex activity. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 24. pp. 10314-10328.
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