Synthesis and in vitro stability of amino acid prodrugs of 6-β-naltrexol for microneedle-enhanced transdermal delivery

Bioorg Med Chem Lett. 2014 Nov 15;24(22):5212-5. doi: 10.1016/j.bmcl.2014.09.072. Epub 2014 Oct 2.

Abstract

A small library of amino acid ester prodrugs of 6-β-naltrexol (NTXOL, 1) was prepared in order to investigate the candidacy of these prodrugs for microneedle-enhanced transdermal delivery. Six amino acid ester prodrugs were synthesized (6a-f). 6b, 6d, and 6 e were stable enough at skin pH (pH 5.0) to move forward to studies in 50% human plasma. The lead compound (6 e) exhibited the most rapid bioconversion to NTXOL in human plasma (t1/2 = 2.2 ± 0.1h).

Keywords: Amino acid esters; Microneedles; Prodrugs; Stability; Transdermal.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Cutaneous
  • Amino Acids / administration & dosage
  • Amino Acids / chemical synthesis
  • Drug Delivery Systems / methods*
  • Drug Stability
  • Humans
  • Naltrexone / administration & dosage
  • Naltrexone / analogs & derivatives*
  • Naltrexone / chemical synthesis
  • Needles
  • Prodrugs / administration & dosage*
  • Prodrugs / chemical synthesis*
  • Skin Absorption / drug effects
  • Skin Absorption / physiology

Substances

  • Amino Acids
  • Prodrugs
  • 6 beta-hydroxynaltrexone
  • Naltrexone