Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors

J Med Chem. 2017 Dec 14;60(23):9790-9806. doi: 10.1021/acs.jmedchem.7b01255. Epub 2017 Nov 22.

Abstract

N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trypanosoma brucei (T. brucei), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. brucei NMT as a promising druggable target for the treatment of HAT in both stages 1 and 2 of the disease. We report on the use of the previously reported DDD85646 (1) as a starting point for the design of a class of potent, brain penetrant inhibitors of T. brucei NMT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / antagonists & inhibitors*
  • Acyltransferases / metabolism
  • Aminopyridines / chemical synthesis
  • Aminopyridines / chemistry*
  • Aminopyridines / pharmacokinetics
  • Aminopyridines / pharmacology*
  • Animals
  • Brain / metabolism
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Mice
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / chemistry*
  • Trypanocidal Agents / pharmacokinetics
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosoma brucei brucei / enzymology*
  • Trypanosomiasis, African / drug therapy*
  • Trypanosomiasis, African / metabolism

Substances

  • Aminopyridines
  • DDD 85646
  • Enzyme Inhibitors
  • Sulfonamides
  • Trypanocidal Agents
  • Acyltransferases
  • glycylpeptide N-tetradecanoyltransferase