N-(Pivaloyloxy)alkoxy-carbonyl Prodrugs of the Glutamine Antagonist 6-Diazo-5-oxo-l-norleucine (DON) as a Potential Treatment for HIV Associated Neurocognitive Disorders

J Med Chem. 2017 Aug 24;60(16):7186-7198. doi: 10.1021/acs.jmedchem.7b00966. Epub 2017 Aug 14.

Abstract

Aberrant excitatory neurotransmission associated with overproduction of glutamate has been implicated in the development of HIV-associated neurocognitive disorders (HAND). The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 14) attenuates glutamate synthesis in HIV-infected microglia/macrophages, offering therapeutic potential for HAND. We show that 14 prevents manifestation of spatial memory deficits in chimeric EcoHIV-infected mice, a model of HAND. 14 is not clinically available, however, because its development was hampered by peripheral toxicities. We describe the synthesis of several substituted N-(pivaloyloxy)alkoxy-carbonyl prodrugs of 14 designed to circulate inert in plasma and be taken up and biotransformed to 14 in the brain. The lead prodrug, isopropyl 6-diazo-5-oxo-2-(((phenyl(pivaloyloxy)methoxy)carbonyl)amino)hexanoate (13d), was stable in swine and human plasma but liberated 14 in swine brain homogenate. When dosed systemically in swine, 13d provided a 15-fold enhanced CSF-to-plasma ratio and a 9-fold enhanced brain-to-plasma ratio relative to 14, opening a possible clinical path for the treatment of HAND.

MeSH terms

  • Aminocaproates / administration & dosage
  • Aminocaproates / chemical synthesis
  • Aminocaproates / pharmacology*
  • Animals
  • Azo Compounds / administration & dosage
  • Azo Compounds / chemical synthesis
  • Azo Compounds / pharmacology*
  • Blood / metabolism
  • Brain / metabolism
  • Diazooxonorleucine / administration & dosage
  • Diazooxonorleucine / pharmacology*
  • Drug Stability
  • Female
  • Glutamic Acid / metabolism
  • Glutaminase / antagonists & inhibitors
  • HIV Infections / complications
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Neurocognitive Disorders / drug therapy*
  • Neurocognitive Disorders / etiology
  • Nootropic Agents / administration & dosage
  • Nootropic Agents / chemical synthesis
  • Nootropic Agents / pharmacology*
  • Prodrugs / administration & dosage
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacology*
  • Swine
  • Viral Load / drug effects

Substances

  • Aminocaproates
  • Azo Compounds
  • Nootropic Agents
  • Prodrugs
  • isopropyl 6-diazo-5-oxo-2-(((phenyl(pivaloyloxy)methoxy)carbonyl)amino)hexanoate
  • Diazooxonorleucine
  • Glutamic Acid
  • Glutaminase