title: Discovery of potent, balanced and orally active dual NK1/NK3 receptor ligands.
abstract: 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.
authors.affiliation: F. Hoffmann-La Roche Ltd, Pharma Research, CH-4070 Basel, Switzerland. jens-uwe.peters@roche.com
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Peters
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoffmann
authors.forename: Patrick
authors.initials: P
authors.lastname: Schnider
authors.forename: Heinz
authors.initials: H
authors.lastname: Stadler
authors.forename: Andreas
authors.initials: A
authors.lastname: Koblet
authors.forename: André
authors.initials: A
authors.lastname: Alker
authors.forename: Sonia Maria
authors.initials: SM
authors.lastname: Poli
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Ballard
authors.forename: Will
authors.initials: W
authors.lastname: Spooren
authors.forename: Lucinda
authors.initials: L
authors.lastname: Steward
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sleight
mesh_terms: D000284:Administration, Oral; D000818:Animals; D055808:Drug Discovery; D008024:Ligands; D008958:Models, Molecular; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D008024:Ligands; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D018042:Receptors, Neurokinin-3