title: Synthesis and pharmacological characterization of bicyclic triple reuptake inhibitor 3-aryl octahydrocyclopenta[c]pyrrole analogues.
abstract: The present work expands the chemical space known to offer potent inhibition of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) and discloses novel bicyclic octahydrocyclopenta[c]pyrrole and octahydro-1H-isoindole scaffolds as potent triple reuptake inhibitors (TRIs) for the potential treatment of depression. Optimized compounds 22a (SERT, NET, DAT, IC(50) = 20, 109, 430 nM), 23a (SERT, NET, DAT, IC(50) = 29, 85, 168 nM), and 26a (SERT, NET, DAT, IC(50) = 53, 150, 140 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 10 and 30 mpk PO, and were not generally motor stimulants at doses ranging from 1 to 30 mpk PO. Moderate in vitro cytochrome P450 (CYP) and potassium ion channel Kv11.1 (hERG) inhibition were uncovered as potential liabilities for the chemical series.
authors: Discovery and Early Clinical Research, Sunovion Pharmaceuticals, Marlborough, Massachusetts 01752, United States. Liming.shao@sunovion.com
authors: Liming
authors: L
authors: Shao
authors: Michael C
authors: MC
authors: Hewitt
authors: Scott C
authors: SC
authors: Malcolm
authors: Fengjiang
authors: F
authors: Wang
authors: Jianguo
authors: J
authors: Ma
authors: Una C
authors: UC
authors: Campbell
authors: Nancy A
authors: NA
authors: Spicer
authors: Sharon R
authors: SR
authors: Engel
authors: Larry W
authors: LW
authors: Hardy
authors: Zhi-Dong
authors: ZD
authors: Jiang
authors: Rudy
authors: R
authors: Schreiber
authors: Kerry L
authors: KL
authors: Spear
authors: Mark A
authors: MA
authors: Varney
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D020128:Inhibitory Concentration 50; D054833:Isoindoles / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D054833:Isoindoles; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011758:Pyrroles; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors