Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate.
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.
Neurosciences Centre of Excellence for Drug Discovery, Chemical Development and Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy. Electronic address: romano.difabio@aptuit.com.
Romano
R
Di Fabio
Giuseppe
G
Alvaro
Simone
S
Braggio
Renzo
R
Carletti
Philip A
PA
Gerrard
Cristiana
C
Griffante
Carla
C
Marchioro
Alfonso
A
Pozzan
Sergio
S
Melotto
Alessandro
A
Poffe
Laura
L
Piccoli
Emiliangelo
E
Ratti
Elvira
E
Tranquillini
Michael
M
Trower
Simone
S
Spada
Mauro
M
Corsi
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001522:Behavior, Animal / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D005260:Female; D005849:Gerbillinae; D006207:Half-Life; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D064729:Neurokinin-1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D010879:Piperazines / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014508:Urea
D000928:Antidepressive Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C531951:casopitant; D014508:Urea; C584555:orvepitant
CDI; CHO; CINV; CNS; CRC; Central nervous system; Chinese hamster ovary; Clp; FDA; FLIPR; G protein-coupled receptor; G-protein coupled receptor; GFT; GPCR; HTT; NK; Neurokinin; PoC; SAD; SAR; SI; SP; SSRIs; Substance P; THF; carbonyldiimidazole; central nervous system; chemotherapy-induced nausea and vomiting; clearance plasmatic; concentration–response curve; fluorescence imaging plate reader; food and drug administration; gerbil foot tapping; human threat test; i.v.; intravenous; neurokinin; p.o.; per os; prove of concept; selective serotonin reuptake inhibitors; social anxiety disorders; social interaction; structure–activity relationship; substance P; tetrahydrofuran