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.
Ramin Faghih  1 ,  Sujatha M Gopalakrishnan ,  Jens Halvard Gronlien ,  John Malysz ,  Clark A Briggs ,  Caroline Wetterstrand ,  Hilde Ween ,  Michael P Curtis ,  Kathy A Sarris ,  Gregory A Gfesser ,  Rachid El-Kouhen ,  Holly M Robb ,  Richard J Radek ,  Kennan C Marsh ,  William H Bunnelle ,  Murali Gopalakrishnan
Affiliations
  • 1. Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. [email protected]
PMID: 19419141 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.