Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK 1 receptor antagonist clinical candidate Romano Di Fabio ⇑,  , Giuseppe Alvaro à , Simone Braggio   , Renzo Carletti   , Philip A. Gerrard   , Cristiana Griffante   , Carla Marchioro   , Alfonso Pozzan   , Sergio Melotto § , Alessandro Poffe   , Laura Piccoli   , Emiliangelo Ratti k , Elvira Tranquillini – , Michael Trower k , Simone Spada   , Mauro Corsi   Neurosciences Centre of Excellence for Drug Discovery, Chemical Development and Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy article info Article history: Received 6 June 2013 Revised 29 August 2013 Accepted 1 September 2013 Available online 11 September 2013 Keywords: Neurokinin Substance P G-protein coupled receptor Central nervous system abstract The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 recep- tor (NK 1 ) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK 1 receptor antagonist aprepitant has been approved as a ther- apeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK 1 receptor antagonists had yet to be realized; therefore clinical evidence that NK 1 receptor antagonists may be effective in major depression disorder, resulted in a sig- nificant further investment in discovering novel CNS penetrant druggable NK 1 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 NK 1 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 NK 1 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 NK 1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction The undecapeptide substance P (SP) is one of the most studied neurotransmitters in the CNS. Its pharmacological action is medi- ated by the preferential interaction with the 7-transmembrane G-coupled protein (GPCR) neurokinin 1 (NK 1 ) receptor. This recep- tor belongs to the tachykinin superfamily that consists of three receptor subtypes (NK 1 , NK 2 and NK 3 ) and is expressed widely in the mammalian nervous system, spinal cord and peripheral tissues. 1–3 A large body of both pre-clinical and clinical evidence has linked the NK 1 receptor/SP system with a plethora of patholog- ical conditions, ranging from pain, migraine, asthma, nausea, inflammatory bowel syndrome, cancer and urinary incontinence to anxiety and depression. 4–13 Since the publication of the first non-peptidic NK 1 receptor antagonist in the early 1990s, there has been much effort to discover drug-like NK 1 receptor antagonists and bring them through clinical trials to the market. To date aprepitant 14 is the first and only NK 1 receptor antagonist to gain approval by the FDA; this 0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmc.2013.09.001 Abbreviations: NK, neurokinin; SP, substance P; GPCR, G protein-coupled receptor; CNS, central nervous system; SAD, social anxiety disorders; CINV, chemotherapy-induced nausea and vomiting; PoC, prove of concept; SAR, struc- ture–activity relationship; CDI, carbonyldiimidazole; THF, tetrahydrofuran; CHO, Chinese hamster ovary; FLIPR, fluorescence imaging plate reader; GFT, gerbil foot tapping; CRC, concentration–response curve; SSRIs, selective serotonin reuptake inhibitors; HTT, human threat test; SI, social interaction; FDA, food and drug administration; i.v., intravenous; p.o., per os; Clp, clearance plasmatic. ⇑ Corresponding author. Tel.: +39 0458218879. E-mail address: romano.difabio@aptuit.com (R. Di Fabio).   Present address: Aptuit S.r.l., Via A. Fleming 4, 37135 Verona, Italy. à Present address: Autifony S.r.l., Via A. Fleming 4, 37135 Verona, Italy. § Present address: Ablicon S.r.l., Via L. Einaudi 29, 62012 Civitanova Marche (MC), Italy. – Present address: Sandoz Industrial Products S.p.A., Corso Verona 165, 38068 Rovereto (TN), Italy. k Present address: NeRRe Therapeutics Ltd, Gunnels Wood Road, Stevenage SG1 2FX, UK. Bioorganic & Medicinal Chemistry 21 (2013) 6264–6273 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc