Discovery of 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (TC-6683, AZD1446), a novel highly selective alpha4beta2 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders.

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Mazurov AA, Miao L, Bhatti BS, Strachan JP, Akireddy S, Murthy S, Kombo D, Xiao YD, Hammond P, Zhang J, Hauser TA, Jordan KG, Miller CH, Speake JD, Gatto GJ, Yohannes D

J Med Chem. 2012 Nov 8;55(21):9181-94. doi: 10.1021/jm3006542. Epub 2012 Jul 27.

PubMed ID

22793665 [ View in PubMed

]

Abstract

Diversification of essential nicotinic cholinergic pharmacophoric elements, i.e., cationic center and hydrogen bond acceptor, resulted in the discovery of novel potent alpha4beta2 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 alpha4beta2 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Nicotine	Neuronal acetylcholine receptor subunit beta-2	Ki (nM)	2	N/A	N/A	Details
Nicotine	Neuronal acetylcholine receptor subunit beta-2	EC 50 (nM)	3000	N/A	N/A	Details