The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties.