During a program directed at selective NK(1) receptor antagonists, we serendipitously discovered an NK(1) receptor ligand with additional affinity for the NK(3) receptor. Recognising an opportunity for a drug discovery program aiming for dual NK(1)/NK(3) receptor antagonists, we prepared a series of analogues from a novel, versatile building block. From this series emerged compounds with high and balanced affinities for the NK(1) and the NK(3) receptors. Typical representatives of this series were active in the gerbil foot tapping assay after oral administration.
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Design, Synthesis, and Optimization of Balanced Dual NK1/NK3 Receptor Antagonists.
ACS Med Chem Lett
May 2014
Neuroscience Chemistry Research Unit, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
In connection with a program directed at potent and balanced dual NK1/NK3 receptor ligands, a focused exploration of an original class of peptidomimetic derivatives was performed. The rational design and molecular hybridization of a novel phenylalanine core series was achieved to maximize the in vitro affinity and antagonism at both human NK1 and NK3 receptors. This study led to the identification of a new potent dual NK1/NK3 antagonist with pK i values of 8.
View Article and Find Full Text PDFDesign and synthesis of potential dual NK(1)/NK(3) receptor antagonists.
Bioorg Med Chem Lett
January 2014
Neuroscience Chemistry Research Unit, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
The tachykinin NK1 and NK3 receptors are a novel drug target for schizophrenia in order to treat not only the positive and cognitive symptoms, but also the associated co-morbid depression and sleep disturbances associated with the disease. A novel class of peptidomimetic derivatives based on a versatile phenylglycine central core was synthesized and tested in vitro as dual NK1/NK3 receptor antagonists. From this series emerged compounds with good NK1 receptor affinity, although only modest dual NK1/NK3 receptor affinity was observed with one of these analogs.
View Article and Find Full Text PDFPharmacokinetics and central nervous system effects of the novel dual NK1 /NK3 receptor antagonist GSK1144814 in alcohol-intoxicated volunteers.
Br J Clin Pharmacol
May 2013
Centre for Human Drug Research, Leiden, The Netherlands.
Aims: Antagonism of both NK1 and NK3 receptors may be an effective strategy in the pharmacotherapy of schizophrenia, drug addiction or depression. GSK1144814 is a novel selective dual NK1 /NK3 receptor antagonist. The potential influence of GSK1144814 on the effects of alcohol was investigated.
View Article and Find Full Text PDFIdentification of a crucial amino acid in the helix position 6.51 of human tachykinin neurokinin 1 and 3 receptors contributing to the insurmountable mode of antagonism by dual NK₁/NK₃ antagonists.
J Med Chem
June 2012
Medicinal Chemistry, Pharma Research and Early Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, CH4070, Basel, Switzerland.
The neurokinins are neuropeptides that elicit their effect through three GPCRs called NK(1), NK(2), and NK(3). Compounds 5 and 6 are dual hNK(1) (K(i) of 0.7 and 0.
View Article and Find Full Text PDFIdentification of novel NK1/NK3 dual antagonists for the potential treatment of schizophrenia.
Bioorg Med Chem Lett
November 2011
GlaxoSmithKline Medicines Research Centre, Neurosciences Centre of Excellence for Drug Discovery, Via Fleming 4, 37135 Verona, Italy.
During the lead optimization of NK(1)/NK(3) receptor antagonists program, a focused exploration of molecules bearing a lactam moiety was performed. The aim of the investigation was to identify the optimal position of the carbonyl and hydroxy methyl group in the lactam moiety, in order to maximize the in vitro affinity and the level of insurmountable antagonism at both NK(1) and NK(3) receptors. The synthesis and biological evaluation of these novel lactam derivatives, with potent and balanced NK(1)/NK(3) activity, were reported in this paper.
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