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Identification of clinically viable quinolinol inhibitors of botulinum neurotoxin A light chain

Academic Article
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Overview

authors

  • Caglic, D.
  • Krutein, M. C.
  • Bompiani, K. M.
  • Barlow, D. J.
  • Benoni, G.
  • Pelletier, J. C.
  • Reitz, A. B.
  • Lairson, Luke
  • Houseknecht, K. L.
  • Smith, G. R.
  • Dickerson, Tobin

publication date

  • February 2014

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • Botulinum neurotoxins (BoNT) are the most potent toxins known and a significant bioterrorist threat. Few small molecule compounds have been identified that are active in cell-based or animal models, potentially due to toxin enzyme plasticity. Here we screened commercially available quinolinols, as well as synthesized hydroxyquinolines. Seventy-two compounds had IC50 values below 10 μM, with the best compound exhibiting submicromolar inhibition (IC50 = 0.8 μM). Structure-activity relationship trends showed that the enzyme tolerates various substitutions at R1 but has a clear preference for bulky aryl amide groups at R2, while methylation at R3 increased inhibitor potency. Evaluation of the most potent compounds in an ADME panel showed that these compounds possess poor solubility at pH 6.8, but display excellent solubility at low pH, suggesting that oral dosing may be possible. Our data show the potential of quinolinol compounds as BoNT therapeutics due to their good in vitro potencies and favorable ADME properties.

subject areas

  • Animals
  • Botulinum Toxins, Type A
  • Catalytic Domain
  • Humans
  • Hydrogen-Ion Concentration
  • Hydroxyquinolines
  • In Vitro Techniques
  • Microsomes, Liver
  • Rats
  • Rats, Sprague-Dawley
  • Solubility
  • Structure-Activity Relationship
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Identity

PubMed Central ID

  • PMC3983388

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm4012164

PubMed ID

  • 24387280
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Additional Document Info

start page

  • 669

end page

  • 676

volume

  • 57

issue

  • 3

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