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Biaryls as potent, tunable dual neurokinin 1 receptor antagonists and serotonin transporter inhibitors.

Abstract：

:Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11-84%) via dose selection.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Degnan AP,Tora GO,Han Y,Rajamani R,Bertekap R,Krause R,Davis CD,Hu J,Morgan D,Taylor SJ,Krause K,Li YW,Mattson G,Cunningham MA,Taber MT,Lodge NJ,Bronson JJ,Gillman KW,Macor JE

doi

10.1016/j.bmcl.2015.04.098

subject

Has Abstract

pub_date

2015-08-01 00:00:00

pages

3039-43

issue

15

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(15)00443-6

journal_volume

25

pub_type

杂志文章

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