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.
Subject(s)
Pyrroles/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacology , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Inhibitory Concentration 50 , Isoindoles/chemical synthesis , Isoindoles/pharmacology , Mice , Motor Activity/drug effects , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Pyrroles/pharmacology , Rats , Serotonin Plasma Membrane Transport Proteins/drug effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
The current work discloses a novel cyclohexylarylamine chemotype with potent inhibition of the serotonin, norepinephrine, and dopamine transporters and potential for treatment of major depressive disorder. Optimized compounds 1 (SERT, NET, DAT, IC(50)=169, 85, 21 nM) and 42 (SERT, NET, DAT IC(50)=34, 295, 90 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 30 mpk po and were not general motor stimulants.
Subject(s)
Amines/chemical synthesis , Dopamine Uptake Inhibitors , Drug Design , Methane/chemical synthesis , Norepinephrine , Serotonin , Amines/chemistry , Amines/pharmacology , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Cyclization , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacology , Inhibitory Concentration 50 , Methane/chemistry , Methane/pharmacology , Mice , Molecular Structure , Norepinephrine/chemical synthesis , Norepinephrine/chemistry , Norepinephrine/pharmacology , Rats , Serotonin/chemical synthesis , Serotonin/chemistry , Serotonin/pharmacology , StereoisomerismABSTRACT
Novel chiral cyclohexylaryl amines were developed with potent reuptake inhibition against the serotonin, norepinephrine and dopamine transporters and activity at 10 and 30 mpk PO in the mouse tail suspension test. Prototype compound 31 (SERT, NET, DAT IC(50) ≤ 1, 21, 28 nM) was highly brain penetrant, had minimal CYP and hERG inhibition, and represents a previously undisclosed architecture with potential for treatment of major depressive disorder.
Subject(s)
Amines/chemical synthesis , Dopamine Uptake Inhibitors , Drug Design , Norepinephrine , Serotonin , Amines/chemistry , Amines/pharmacology , Animals , Cyclization , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacology , Inhibitory Concentration 50 , Mice , Molecular Structure , Norepinephrine/chemical synthesis , Norepinephrine/chemistry , Norepinephrine/pharmacology , Serotonin/chemical synthesis , Serotonin/chemistry , Serotonin/pharmacology , StereoisomerismABSTRACT
The present work describes a series of novel chiral amines that potently inhibit the in vitro reuptake of serotonin, norepinephrine and dopamine (triple reuptake inhibitors) and were active in vivo in a mouse model predictive of antidepressant like activity. The detailed synthesis and in vitro activity and ADME profile of compounds is described, which represent a previously undisclosed triple reuptake inhibitor chemotype.
Subject(s)
Naphthalenes/chemical synthesis , Naphthalenes/pharmacology , Neurotransmitter Uptake Inhibitors/chemical synthesis , Neurotransmitter Uptake Inhibitors/pharmacology , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacology , Disease Models, Animal , Dopamine/metabolism , Drug Evaluation, Preclinical , Mice , Norepinephrine/metabolism , Serotonin/metabolismABSTRACT
The present work describes a series of novel tetrahydroquinoline amines that potently inhibit the in vitro reuptake of serotonin and dopamine (dual reuptake inhibitors). The compounds are structurally related to a series we disclosed previously, but are improved with respect to cytochrome P-450 enzyme (CYP) and potassium ion channel Kv11.1 (hERG) inhibition and synthetic accessibility. The detailed synthesis and in vitro activity and ADME profile of the compounds is described, which represent a previously undisclosed dual reuptake inhibitor chemotype.
