title: Design, synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain.
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.
authors.affiliation: Roche Palo Alto LLC, Department of Medicinal Chemistry, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. matthew.lucas@roche.com
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Lucas
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Weikert
authors.forename: David S
authors.initials: DS
authors.lastname: Carter
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Cai
authors.forename: Robert
authors.initials: R
authors.lastname: Greenhouse
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Iyer
authors.forename: Clara J
authors.initials: CJ
authors.lastname: Lin
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Lee
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Madera
authors.forename: Amy
authors.initials: A
authors.lastname: Moore
authors.forename: Kerem
authors.initials: K
authors.lastname: Ozboya
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Schoenfeld
authors.forename: Sandra
authors.initials: S
authors.lastname: Steiner
authors.forename: Yansheng
authors.initials: Y
authors.lastname: Zhai
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Lynch
mesh_terms: 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
chemical_list: 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