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.
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.
Targacept, Inc., Winston Salem, North Carolina 27101, United States. anatoly.mazurov@targacept.com
Anatoly A
AA
Mazurov
Lan
L
Miao
Balwinder S
BS
Bhatti
Jon-Paul
JP
Strachan
Srinivasa
S
Akireddy
Srinivasa
S
Murthy
David
D
Kombo
Yun-de
YD
Xiao
Philip
P
Hammond
Jenny
J
Zhang
Terry A
TA
Hauser
Kristen G
KG
Jordan
Craig H
CH
Miller
Jason D
JD
Speake
Gregory J
GJ
Gatto
Daniel
D
Yohannes
D000818:Animals; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003072:Cognition Disorders / Q000188:drug therapy*; D006224:Cricetinae; D003412:Cricetulus; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D008297:Male; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C578484:3-(5-chloro-2-furoyl)-3,7-diazabicyclo(3.3.0)octane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2