Designing rapid onset selective serotonin re-uptake inhibitors. 2: structure-activity relationships of substituted (aryl)benzylamines.
A series of substituted benzylamines 2-48 were prepared as part of a strategy to identify structurally differentiated and synthetically more accessible selective serotonin reuptake inhibitors, relative to clinical candidate 1. In particular, 44 and 48; demonstrated low nanomolar potency and good selectivity, in a structurally simplified template and, in vivo, very low Vdu, significantly lower than l, and a more rapid T(max), consistent with our clinical objectives.
Middleton
Donald S
DS
Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK. don.s.middleton@pfizer.com
Andrews
Mark
M
Glossop
Paul
P
Gymer
Geoffrey
G
Hepworth
David
D
Jessiman
Alan
A
Johnson
Patrick S
PS
Mackenny
Malcolm
M
Pitcher
Michael J
MJ
Rooker
Tony
T
Stobie
Alan
A
Tang
Kim
K
Morgan
Paul
P
D001596:Benzylamines / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D008968:Molecular Conformation; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000737:chemistry / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001596:Benzylamines; D011985:Receptors, Serotonin; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors