Design, synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain.
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.
Lucas
Matthew C
MC
Roche Palo Alto LLC, Department of Medicinal Chemistry, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. matthew.lucas@roche.com
Weikert
Robert J
RJ
Carter
David S
DS
Cai
Hai-Ying
HY
Greenhouse
Robert
R
Iyer
Pravin S
PS
Lin
Clara J
CJ
Lee
Eun Kyung
EK
Madera
Ann Marie
AM
Moore
Amy
A
Ozboya
Kerem
K
Schoenfeld
Ryan C
RC
Steiner
Sandra
S
Zhai
Yansheng
Y
Lynch
Stephen M
SM
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D003863:Depression / Q000188:drug therapy; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D000929:Antidepressive Agents, Tricyclic; D004298:Dopamine; D018765:Dopamine Uptake Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D009638:Norepinephrine; D011759:Pyrrolidines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C032519:pyrrolidine