Synthesis and SAR studies of 1,4-diazabicyclo[3.2.2]nonane phenyl carbamates--subtype selective, high affinity alpha7 nicotinic acetylcholine receptor agonists.
The synthesis and SAR studies about the bicyclic amine, carbamate linker and aromatic ring of a 1,4-diazabicyclo[3.2.2]nonane phenyl carbamate series of alpha7 nAChR agonists is described. The development of the medicinal chemistry strategy and SAR which led to the identification of 5 and 7aa as subtype selective, high affinity alpha7 agonists as excellent leads for further evaluation is discussed, along with key physicochemical and pharmacokinetic data highlighting their lead potential.
O'Donnell
Christopher J
CJ
Neuroscience Medicinal Chemistry, Pfizer Global Research & Development, Groton, CT 06340, United States. christopher.j.odonnell@pfizer.com
Peng
Langu
L
O'Neill
Brian T
BT
Arnold
Eric P
EP
Mather
Robert J
RJ
Sands
Steven B
SB
Shrikhande
Alka
A
Lebel
Lorraine A
LA
Spracklin
Douglas K
DK
Nedza
Frank M
FM
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002460:Cell Line; D006801:Humans; D008297:Male; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D048448:Phenylcarbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
C543968:1,4-diazabicyclo(3.2.2)nonane phenyl carbamate; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002219:Carbamates; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D048448:Phenylcarbamates; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor