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 Tmax, consistent with our clinical objectives.