Discovery of potent, balanced and orally active dual NK1/NK3 receptor ligands.
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.
Peters
Jens-Uwe
JU
F. Hoffmann-La Roche Ltd, Pharma Research, CH-4070 Basel, Switzerland. jens-uwe.peters@roche.com
Hoffmann
Torsten
T
Schnider
Patrick
P
Stadler
Heinz
H
Koblet
Andreas
A
Alker
André
A
Poli
Sonia Maria
SM
Ballard
Theresa M
TM
Spooren
Will
W
Steward
Lucinda
L
Sleight
Andrew J
AJ
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
D008024:Ligands; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D018042:Receptors, Neurokinin-3