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

Matthew C Lucas; Robert J Weikert; David S Carter; Hai-Ying Cai; Robert Greenhouse; Pravin S Iyer; Clara J Lin; Eun Kyung Lee; Ann Marie Madera; Amy Moore; Kerem Ozboya; Ryan C Schoenfeld; Sandra Steiner; Yansheng Zhai; Stephen M Lynch

doi:10.1016/j.bmcl.2010.07.020

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

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

Authors

Matthew C Lucas¹, Robert J Weikert, David S Carter, Hai-Ying Cai, Robert Greenhouse, Pravin S Iyer, Clara J Lin, Eun Kyung Lee, Ann Marie Madera, Amy Moore, Kerem Ozboya, Ryan C Schoenfeld, Sandra Steiner, Yansheng Zhai, Stephen M Lynch

Affiliation

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

PMID: 20691589
DOI: 10.1016/j.bmcl.2010.07.020

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.

MeSH terms

Animals
Antidepressive Agents, Tricyclic / chemical synthesis
Antidepressive Agents, Tricyclic / chemistry
Antidepressive Agents, Tricyclic / pharmacokinetics
Antidepressive Agents, Tricyclic / pharmacology*
Caco-2 Cells
Depression / drug therapy
Dopamine / metabolism*
Dopamine Uptake Inhibitors / chemical synthesis
Dopamine Uptake Inhibitors / chemistry
Dopamine Uptake Inhibitors / pharmacokinetics
Dopamine Uptake Inhibitors / pharmacology
Drug Design
Humans
Neurotransmitter Uptake Inhibitors / chemical synthesis
Neurotransmitter Uptake Inhibitors / chemistry
Neurotransmitter Uptake Inhibitors / pharmacokinetics
Neurotransmitter Uptake Inhibitors / pharmacology*
Norepinephrine / metabolism*
Pain / drug therapy
Pyrrolidines / chemical synthesis
Pyrrolidines / chemistry
Pyrrolidines / pharmacokinetics
Pyrrolidines / pharmacology*
Rats
Selective Serotonin Reuptake Inhibitors / chemical synthesis
Selective Serotonin Reuptake Inhibitors / chemistry
Selective Serotonin Reuptake Inhibitors / pharmacokinetics
Selective Serotonin Reuptake Inhibitors / pharmacology
Serotonin / metabolism*

Substances

Antidepressive Agents, Tricyclic
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Pyrrolidines
Serotonin Uptake Inhibitors
Serotonin
pyrrolidine
Dopamine
Norepinephrine