Novel alpha-7 nicotinic acetylcholine receptor agonists containing a urea moiety: identification and characterization of the potent, selective, and orally efficacious agonist 1-[6-(4-fluorophenyl)pyridin-3-yl]-3-(4-piperidin-1-ylbutyl) urea (SEN34625/WYE-103914)

  • J Med Chem. 2010 Jun 10;53(11):4379-89. doi: 10.1021/jm901692q.
Chiara Ghiron  1 ,  Simon N Haydar ,  Suzan Aschmies ,  Hendrick Bothmann ,  Cristiana Castaldo ,  Giuseppe Cocconcelli ,  Thomas A Comery ,  Li Di ,  John Dunlop ,  Tim Lock ,  Angela Kramer ,  Dianne Kowal ,  Flora Jow ,  Steve Grauer ,  Boyd Harrison ,  Salvatore La Rosa ,  Laura Maccari ,  Karen L Marquis ,  Iolanda Micco ,  Arianna Nencini ,  Joanna Quinn ,  Albert J Robichaud ,  Renza Roncarati ,  Carla Scali ,  Georg C Terstappen ,  Elisa Turlizzi ,  Michela Valacchi ,  Maurizio Varrone ,  Riccardo Zanaletti ,  Ugo Zanelli
Affiliations
  • 1. Siena Biotech SpA, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy. [email protected]
PMID: 20465311 DOI: 10.1021/jm901692q
Abstract

Alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4-18) of the alpha7 nAChR deriving from our continuing efforts in the areas of Alzheimer's disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the alpha7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.