Synthesis and Pharmacological Characterization of Bicyclic Triple Reuptake Inhibitor 3-Aryl Octahydrocyclopenta[c]pyrrole Analogues

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• 作者：Liming Shao ; Michael C. Hewitt ; Scott C. Malcolm ; Fengjiang Wang ; Jianguo Ma ; Una C. Campbell ; Nancy A. Spicer ; Sharon R. Engel ; Larry W. Hardy ; Zhi-Dong Jiang ; Rudy Schreiber ; Kerry L. Spear ; Mark A. Varney
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 11, 2011
• 年：2011
• 卷：54
• 期：15
• 页码：5283-5295
• 全文大小：1185K
• 年卷期：v.54,no.15(August 11, 2011)
• ISSN：1520-4804

文摘

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, IC₅₀ = 20, 109, 430 nM), 23a (SERT, NET, DAT, IC₅₀ = 29, 85, 168 nM), and 26a (SERT, NET, DAT, IC₅₀ = 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.