Discovery of 3-(5-Chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (TC-6683, AZD1446), a Novel Highly Selective 伪4尾2 Nicotinic Acetylcholine Receptor Agonist for the Treatment of Cognitive Disorders

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• 作者：Anatoly A. Mazurov ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：55
• 期：21
• 页码：9181-9194
• 全文大小：563K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

Diversification of essential nicotinic cholinergic pharmacophoric elements, i.e., cationic center and hydrogen bond acceptor, resulted in the discovery of novel potent 伪4尾2 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 伪4尾2 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鈥檚 disease.