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.

Designing rapid onset selective serotonin re-uptake inhibitors. Part 1: Structure-activity relationships of substituted (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthaleneamine.

A series of sertraline analogues 4-39 which possess polar groups on the fused tetrahydronaphthalene ring, targeting reduced V(d) as a strategy to reduce T(max) and increase rate of elevation of central 5-HT levels, were prepared. These studies led to the successful identification of 22a, which demonstrated equivalent pharmacology and metabolic stability to 1, but which possessed greatly reduced V(d) leading to significantly shorter T(max), in rat pharmacokinetic studies.