☆ 4.7 Article

Discovery of 6-substituted indole-3-glyoxylamides as lead antiprion agents with enhanced cell line activity, improved microsomal stability and low toxicity

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2011)

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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 46, 期 9, 页码 4125-4132

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ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.06.013

关键词

Drug discovery; Indoles; Prion disease; Structure-activity relationships; Zebrafish

类别

Chemistry, Medicinal

资金

  1. BBSRC [BB/E014119/1]
  2. UK Home Office [HO/04-07-270]
  3. MRC Pump-priming translational research initiative [G0802527]
  4. University of Sheffield
  5. EPSRC [EP/I037296/1] Funding Source: UKRI
  6. MRC [MC_G0802527] Funding Source: UKRI
  7. Biotechnology and Biological Sciences Research Council [BB/E014119/1] Funding Source: researchfish
  8. Engineering and Physical Sciences Research Council [EP/I037296/1] Funding Source: researchfish
  9. Medical Research Council [MC_G0802527] Funding Source: researchfish

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A series of highly potent indole-3-glyoxylamide based antiprion agents was previously characterized, focusing on optimization of structure-activity relationship (SAR) at positions 1-3 of the indole system. New libraries interrogating the SAR at indole C-4 to C-7 now demonstrate that introducing electron-withdrawing substituents at C-6 may improve biological activity by up to an order of magnitude, and additionally confer higher metabolic stability. For the present screening libraries, both the degree of potency and trends in SAR were consistent across two cell line models of prion disease, and the large majority of compounds showed no evidence of toxic effects in zebrafish. The foregoing observations thus make the indole-3-glyoxylamides an attractive lead series for continuing development as potential therapeutic agents against prion disease. (C) 2011 Elsevier Masson SAS. All rights reserved.

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