2. Academic Validation
  3. 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

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

Affiliation

  • 1 Targacept, Inc., Winston Salem, North Carolina 27101, United States. anatoly.mazurov@targacept.com
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.

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