Discovery of 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744) as a novel positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor

J Med Chem. 2009 May 28;52(10):3377-84. doi: 10.1021/jm9003818.

Abstract

The discovery of a series of pyrrole-sulfonamides as positive allosteric modulators (PAM) of alpha7 nAChRs is described. Optimization of this series led to the identification of 19 (A-867744), a novel type II PAM with good potency and selectivity. Compound 19 showed acceptable pharmacokinetic profile across species and brain levels sufficient to modulate alpha7 nAChRs. In a rodent model of sensory gating, 19 normalized gating deficits. These results suggest that 19 represents a novel class of molecules capable of allosteric modulation of the alpha7 nAChRs.

MeSH terms

  • Allosteric Regulation*
  • Animals
  • Brain / metabolism
  • Cells, Cultured
  • Drug Discovery
  • Mice
  • Microsomes
  • Oocytes
  • Patch-Clamp Techniques
  • Pharmacokinetics
  • Pyrroles / pharmacology*
  • Receptors, Nicotinic / drug effects*
  • Sensory Gating / drug effects*
  • Sulfonamides / pharmacology*
  • Xenopus laevis
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide
  • Chrna7 protein, mouse
  • Pyrroles
  • Receptors, Nicotinic
  • Sulfonamides
  • alpha7 Nicotinic Acetylcholine Receptor
  • benzenesulfonamide