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Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents

Academic Article
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Overview

authors

  • Choi, J. Y.
  • Calvet, C. M.
  • Gunatilleke, S. S.
  • Ruiz, C.
  • Cameron, Michael
  • McKerrow, J. H.
  • Podust, L. M.
  • Roush, William

publication date

  • October 2013

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ? 42 nM; EC50 = 0.65 ?M), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 ?M). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.
  • A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 μM). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.

subject areas

  • 14-alpha Demethylase Inhibitors
  • Aminopyridines
  • Animals
  • Crystallography, X-Ray
  • Humans
  • Indoles
  • Mice
  • Microsomes, Liver
  • Molecular Docking Simulation
  • Rats
  • Stereoisomerism
  • Sterol 14-Demethylase
  • Structure-Activity Relationship
  • Trypanocidal Agents
  • Trypanosoma brucei brucei
  • Trypanosoma cruzi
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Identity

PubMed Central ID

  • PMC3864028

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm401067s

PubMed ID

  • 24079662
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Additional Document Info

start page

  • 7651

end page

  • 7668

volume

  • 56

issue

  • 19

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