Designing rapid onset selective serotonin re-uptake inhibitors. 2: structure-activity relationships of substituted (aryl)benzylamines

Donald S Middleton; Mark Andrews; Paul Glossop; Geoffrey Gymer; David Hepworth; Alan Jessiman; Patrick S Johnson; Malcolm Mackenny; Michael J Pitcher; Tony Rooker; Alan Stobie; Kim Tang; Paul Morgan

doi:10.1016/j.bmcl.2008.06.001

Designing rapid onset selective serotonin re-uptake inhibitors. 2: structure-activity relationships of substituted (aryl)benzylamines

Bioorg Med Chem Lett. 2008 Jul 15;18(14):4018-21. doi: 10.1016/j.bmcl.2008.06.001. Epub 2008 Jun 5.

Authors

Donald S Middleton¹, Mark Andrews, Paul Glossop, Geoffrey Gymer, David Hepworth, Alan Jessiman, Patrick S Johnson, Malcolm Mackenny, Michael J Pitcher, Tony Rooker, Alan Stobie, Kim Tang, Paul Morgan

Affiliation

¹ Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK. don.s.middleton@pfizer.com

PMID: 18571404
DOI: 10.1016/j.bmcl.2008.06.001

Abstract

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.

MeSH terms

Benzylamines / chemistry*
Chemistry, Pharmaceutical / methods*
Drug Design
Humans
Inhibitory Concentration 50
Kinetics
Models, Chemical
Molecular Conformation
Receptors, Serotonin / metabolism
Selective Serotonin Reuptake Inhibitors / chemical synthesis*
Selective Serotonin Reuptake Inhibitors / pharmacology*
Serotonin / chemistry
Serotonin / metabolism
Structure-Activity Relationship

Substances

Benzylamines
Receptors, Serotonin
Serotonin Uptake Inhibitors
Serotonin