Synthesis and evaluation of N-acylsulfonamide and N-acylsulfonylurea prodrugs of a prostacyclin receptor agonist

Bioorg Med Chem. 2007 Dec 15;15(24):7720-5. doi: 10.1016/j.bmc.2007.08.052. Epub 2007 Aug 31.

Abstract

N-Acylsulfonamide and N-acylsulfonylurea derivatives of the carboxylic acid prostacyclin receptor agonist 1 were synthesized and their potential as prodrug forms of the carboxylic acid was evaluated in vitro and in vivo. These compounds were converted to the active compound 1 by hepatic microsomes from rats, dogs, monkeys, and humans, and some of the compounds were shown to yield sustained plasma concentrations of 1 when they were orally administered to monkeys. These types of analogues, including NS-304 (2a), are potentially useful prodrugs of 1.

MeSH terms

  • Acetamides / blood
  • Acetamides / chemical synthesis*
  • Acetamides / pharmacokinetics
  • Animals
  • Dogs
  • Drug Evaluation, Preclinical
  • Epoprostenol / analogs & derivatives*
  • Epoprostenol / chemistry*
  • Epoprostenol / pharmacokinetics
  • Haplorhini
  • Humans
  • Male
  • Microsomes / metabolism
  • Molecular Structure
  • Platelet Aggregation Inhibitors / chemical synthesis
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacokinetics
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Prodrugs / pharmacokinetics
  • Pyrazines / blood
  • Pyrazines / chemical synthesis*
  • Pyrazines / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Epoprostenol / agonists*
  • Sulfonylurea Compounds / chemistry*

Substances

  • Acetamides
  • Platelet Aggregation Inhibitors
  • Prodrugs
  • Pyrazines
  • Receptors, Epoprostenol
  • Sulfonylurea Compounds
  • selexipag
  • Epoprostenol