Discovery of 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (TC-6683, AZD1446), a novel highly selective α4β2 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders

  • J Med Chem. 2012 Nov 8;55(21):9181-94. doi: 10.1021/jm3006542.
Anatoly A Mazurov  1 ,  Lan Miao ,  Balwinder S Bhatti ,  Jon-Paul Strachan ,  Srinivasa Akireddy ,  Srinivasa Murthy ,  David Kombo ,  Yun-de Xiao ,  Philip Hammond ,  Jenny Zhang ,  Terry A Hauser ,  Kristen G Jordan ,  Craig H Miller ,  Jason D Speake ,  Gregory J Gatto ,  Daniel Yohannes
Affiliations
  • 1. Targacept, Inc., Winston Salem, North Carolina 27101, United States. [email protected]
PMID: 22793665 DOI: 10.1021/jm3006542
Abstract

Diversification of essential nicotinic cholinergic pharmacophoric elements, i.e., cationic center and hydrogen bond acceptor, resulted in the discovery of novel potent α4β2 nAChR selective agonists comprising a series of N-acyldiazabicycles. Core characteristics of the series are an exocyclic carbonyl moiety as a hydrogen bond acceptor and endocyclic secondary amino group. These features are positioned at optimal distance and with optimal relative spatial orientation to provide near optimal interactions with the receptor. A novel potent and highly selective α4β2 nAChR agonist 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (56, TC-6683, AZD1446) with favorable pharmaceutical properties and in vivo efficacy in animal models has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions and is currently being progressed to phase 2 clinical trials as a treatment for Alzheimer's Disease.

Products