Current treatments of depression are associated with a number of undesirable side effects.  Neurokinin 1 (NK1) antagonists have demonstrated the ability to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in multiple animal models.  A drug which incorporated both activities may offer important tolerability improvements over the current standard of care.  Medicinal chemistry efforts identified a novel, dual-acting biphenyl chemotype which suffered from significant ion channel inhibition and extensive protein binding.  Cues in the structure-activity relationship were pursued to identify heterocyclic replacements which reduced ion channel blockade, protein binding, and molecular weight.  Optimization of this series led to the identification of compounds that achieved the desired target profile and were active in a preclinical model of depression.  Scale-up of the lead compound for toxicological evaluation required the development of an unprecedented heterocycle-directed asymmetric hydrogenation to afford the product in excellent chemical yield and high optical purity.

Discovery of a potent dual neurokinin 1 receptor antagonist and serotonin transporter inhibitor for the treatment of depression

245th National Meeting (2013)

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