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Enhancing the pharmacokinetic properties of botulinum neurotoxin serotype a protease inhibitors through rational design

Academic Article
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Overview

authors

  • Capek, P.
  • Zhang, Y.
  • Barlow, D. J.
  • Houseknecht, K. L.
  • Smith, G. R.
  • Dickerson, Tobin

publication date

  • June 2011

journal

  • ACS Chemical Neuroscience  Journal

abstract

  • Botulinum neurotoxin (BoNT), the etiological agent that causes the neuroparalytic disease botulism, has become a highly studied drug target in light of the potential abuse of this toxin as a weapon of bioterrorism. In particular, small molecule inhibitors of the light chain metalloprotease of BoNT serotype A have received significant attention and a number of small molecule and biologic inhibitors have been reported. However, all small molecules reported have been identified from either primary screens or medicinal chemistry follow-up studies, and the pharmacokinetic profiles of these compounds have not been addressed. In this study, we have removed the pharmacologic liabilities of one of the best compounds reported to date, 2,4-dichlorocinnamate hydroxamic acid, and in the process, uncovered a related class of benzothiophene hydroxamic acids that are significantly more potent inhibitors of the BoNT/A light chain, while also possessing greatly improved ADME properties, with the best compound showing the most potent inhibition of BoNT/A light chain reported (K(i) = 77 nM). Using a strategy of incorporating traditional drug development filters early into the discovery process, potential liabilities in BoNT/A lead compounds have been illuminated and removed, clearing the path for advancement into further pharmacologic optimization and in vivo efficacy testing.
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Research

keywords

  • ADME
  • Botulinum neurotoxin
  • benzothiophene
  • competitive inhibitor
  • zinc metalloprotease
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Identity

PubMed Central ID

  • PMC3129992

International Standard Serial Number (ISSN)

  • 1948-7193

Digital Object Identifier (DOI)

  • 10.1021/cn200021q

PubMed ID

  • 21743830
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Additional Document Info

start page

  • 288

end page

  • 293

volume

  • 2

issue

  • 6

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