Identification of biaryl sulfone derivatives as antagonists of the histamine H₃ receptor: discovery of (R)-1-(2-(4'-(3-methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine (APD916)

Bioorg Med Chem Lett. 2012 Jan 1;22(1):71-5. doi: 10.1016/j.bmcl.2011.11.075. Epub 2011 Nov 30.

Abstract

The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.

MeSH terms

  • Animals
  • Area Under Curve
  • Biphenyl Compounds / chemistry*
  • Biphenyl Compounds / pharmacology*
  • Brain / metabolism
  • Central Nervous System / drug effects
  • Chemistry, Pharmaceutical / methods
  • Drug Design
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / chemistry
  • Histamine Antagonists / chemistry*
  • Histamine Antagonists / pharmacokinetics
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Models, Chemical
  • Pyrrolidines / antagonists & inhibitors
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacology*
  • Rats
  • Receptors, Histamine H3 / chemistry*
  • Sleep / drug effects
  • Sulfones / chemistry*
  • Temperature
  • Wakefulness / drug effects

Substances

  • (R)-1-(2-(4'-(3-methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine
  • Biphenyl Compounds
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Histamine Antagonists
  • Pyrrolidines
  • Receptors, Histamine H3
  • Sulfones
  • pyrrolidine