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Bioorg Med Chem Lett. 2010 Sep 15;20(18):5559-66. doi: 10.1016/j.bmcl.2010.07.020. Epub 2010 Aug 4.

Design, synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain.

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1
Roche Palo Alto LLC, Department of Medicinal Chemistry, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. matthew.lucas@roche.com

Abstract

Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of potency against all three monoamine transporters as well as good human in vitro stability, low drug-drug interaction potential and a decreased propensity for hERG channel binding. Representative compounds from these series displayed good in vivo pharmacokinetics and high monoamine receptor occupancies which are indicators of good brain penetration.

PMID:
20691589
DOI:
10.1016/j.bmcl.2010.07.020
[Indexed for MEDLINE]
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