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Imidazolopiperazines: Lead optimization of the second-generation antimalarial agents

Academic Article
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Overview

authors

  • Nagle, A.
  • Wu, T.
  • Kuhen, K.
  • Gagaring, K.
  • Borboa, R.
  • Francek, C.
  • Chen, Z.
  • Plouffe, D.
  • Lin, X. N.
  • Caldwell, C.
  • Ek, J.
  • Skolnik, S.
  • Liu, F. H.
  • Wang, J. L.
  • Chang, J.
  • Li, C.
  • Liu, B.
  • Hollenbeck, T.
  • Tuntland, T.
  • Isbell, J.
  • Chuan, T.
  • Alper, Phillip
  • Fischli, C.
  • Brun, R.
  • Lakshminarayana, S. B.
  • Rottmann, M.
  • Diagana, T. T.
  • Winzeler, Elizabeth
  • Glynne, R.
  • Tully, D. C.
  • Chatterjee, A. K.

publication date

  • May 2012

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies.

subject areas

  • Animals
  • Antimalarials
  • Biological Availability
  • Caco-2 Cells
  • Humans
  • Imidazoles
  • Malaria, Falciparum
  • Mice
  • Mice, Inbred BALB C
  • Piperazines
  • Plasmodium falciparum
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
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Identity

PubMed Central ID

  • PMC3350218

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm300041e

PubMed ID

  • 22524250
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Additional Document Info

start page

  • 4244

end page

  • 4273

volume

  • 55

issue

  • 9

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