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Discovery of Indazoles as Potent, Orally Active Dual Neurokinin 1 Receptor Antagonists and Serotonin Transporter Inhibitors for the Treatment of Depression
Version 2 2016-11-08, 14:48
Version 1 2016-10-18, 18:35
journal contribution
posted on 2016-10-17, 00:00 authored by Andrew P. Degnan, George O. Tora, Hong Huang, David A. Conlon, Carl D. Davis, Umesh M. Hanumegowda, Xiaoping Hou, Yi Hsiao, Joanna Hu, Rudolph Krause, Yu-Wen Li, Amy E. Newton, Rick L. Pieschl, Joseph Raybon, Thorsten Rosner, Jung-Hui Sun, Matthew T. Taber, Sarah J. Taylor, Michael K. Wong, Huiping Zhang, Nicholas J. Lodge, Joanne J. Bronson, John E. Macor, Kevin W. GillmanCombination
studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective
reuptake inhibitors (SSRIs) have shown promise in preclinical models
of depression. Such a combination may offer important advantages over
the current standard of care. Herein we describe the discovery and
optimization of an indazole-based chemotype to provide a series of
potent dual NK1 receptor antagonists/serotonin transporter (SERT)
inhibitors to overcome issues of ion channel blockade. This effort
culminated in the identification of compound 9, an analogue
that demonstrated favorable oral bioavailability, excellent brain
uptake, and robust in vivo efficacy in a validated depression model.
Over the course of this work, a novel heterocycle-directed asymmetric
hydrogenation was developed to facilitate installation of the key
stereogenic center.
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brain uptakedepression modelcompound 9installationserotonin-selective reuptake inhibitorsvivo efficacyindazole-based chemotypereceptorDepression Combination studiesanalogueDual Neurokinin 1 Receptor AntagonistsSerotonin Transporter InhibitorsSERTNKserieshydrogenationidentificationantagonistSSRIissuecombinationneurokinin 1bioavailabilityIndazoleOrallySuchtransportereffortnovel heterocycle-directedHereinPotention channel blockadeoptimizationpromisestereogenic center
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