ABSTRACT
Sequential modification of the previously identified 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols led to the identification of a new series of 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides that are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound 10b (WYE-114152) had low nanomolar hNET potency (IC(50) = 15 nM) and good selectivity for hNET over hSERT (>430-fold) and hDAT (>548-fold). 10b was additionally bioavailable following oral dosing and demonstrated efficacy in rat models of acute, inflammatory, and neuropathic pain.
Subject(s)
Analgesics/chemical synthesis , Benzothiazoles/chemical synthesis , Cyclic S-Oxides/chemical synthesis , Morpholines/chemical synthesis , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Thiadiazoles/chemical synthesis , Acute Pain/drug therapy , Administration, Oral , Analgesics/chemistry , Analgesics/pharmacology , Animals , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Biological Availability , Cell Line , Chronic Pain/drug therapy , Cricetinae , Cyclic S-Oxides/chemistry , Cyclic S-Oxides/pharmacology , Dogs , Humans , Inflammation/drug therapy , Inflammation/physiopathology , Injections, Intravenous , Male , Morpholines/chemistry , Morpholines/pharmacology , Neuralgia/drug therapy , Rats , Stereoisomerism , Thiadiazoles/chemistry , Thiadiazoles/pharmacologyABSTRACT
Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols which are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound S-17b (WYE-103231) had low nanomolar hNET potency (IC(50) = 1.2 nM) and excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). S-17b additionally had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain.
Subject(s)
Cyclic S-Oxides/chemistry , Cyclic S-Oxides/pharmacology , Drug Discovery/methods , Neurotransmitter Uptake Inhibitors/chemistry , Neurotransmitter Uptake Inhibitors/pharmacology , Norepinephrine/metabolism , Thiadiazoles/chemistry , Thiadiazoles/pharmacology , Animals , Cell Line , Cyclic S-Oxides/chemical synthesis , Cyclic S-Oxides/pharmacokinetics , Female , Humans , Male , Neurotransmitter Uptake Inhibitors/chemical synthesis , Neurotransmitter Uptake Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacokineticsABSTRACT
Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure-activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC(50) = 2.7-6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (SNL) model of neuropathic pain.
Subject(s)
Indoles/pharmacology , Neurotransmitter Uptake Inhibitors/chemistry , Neurotransmitter Uptake Inhibitors/pharmacology , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Propanolamines/pharmacology , Animals , Body Temperature Regulation/drug effects , Female , Indoles/chemical synthesis , Indoles/chemistry , Magnetic Resonance Spectroscopy , Neurotransmitter Uptake Inhibitors/chemical synthesis , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Pain/drug therapy , Propanolamines/chemical synthesis , Propanolamines/chemistry , Rats , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
The potency and selectivity of a series of 1-{(1S)-2-[amino]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol analogues are described. These compounds were prepared to improve in vitro metabolic stability and achieve brain penetration. Compound 13 (WAY-260022, NRI-022) was found to be a potent inhibitor of norepinephrine reuptake and demonstrated excellent selectivity over the serotonin and dopamine transporters. Additionally, 13 exhibited oral efficacy in a rat model of thermoregulatory dysfunction.
ABSTRACT
The discovery of a series of 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles, dual acting norepinephrine reuptake inhibitors (NRIs) and 5-HT(2A) receptor antagonists, is described. The synthesis and structure-activity relationship (SAR) of this novel series of compounds is also presented.
Subject(s)
Indoles/pharmacology , Neurotransmitter Uptake Inhibitors/chemical synthesis , Neurotransmitter Uptake Inhibitors/pharmacology , Norepinephrine/metabolism , Serotonin 5-HT2 Receptor Antagonists , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Biological Transport/drug effects , Cell Line , Humans , Indoles/chemical synthesis , Indoles/metabolism , Neurotransmitter Uptake Inhibitors/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Serotonin Antagonists/metabolism , Structure-Activity RelationshipABSTRACT
Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC(50) values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.
Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Neurotransmitter Uptake Inhibitors/chemistry , Neurotransmitter Uptake Inhibitors/pharmacology , Norepinephrine/metabolism , Administration, Oral , Animals , Behavior, Animal/drug effects , Benzimidazoles/administration & dosage , Benzimidazoles/pharmacokinetics , Biological Transport/drug effects , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Female , Humans , Hyperalgesia/physiopathology , Male , Neurotransmitter Uptake Inhibitors/administration & dosage , Neurotransmitter Uptake Inhibitors/pharmacokinetics , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Propanolamines/chemistry , Rats , Rats, Sprague-Dawley , Serotonin Plasma Membrane Transport Proteins/metabolism , Spinal Nerves/drug effects , Spinal Nerves/physiology , Structure-Activity Relationship , Substrate SpecificityABSTRACT
The SAR of a series of 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols as monoamine reuptake inhibitors, with a goal to improve both potency toward inhibiting the norepinephrine transporter and selectivity over the serotonin transporter, is reported. The effect of specific substitution on both the 3-phenyl group and the indole moiety were explored. This study led to the discovery of compound 20 which inhibited the norepinephrine transporter with an IC50 value of 4 nM while exhibiting 86-fold selectivity over the serotonin transporter.
Subject(s)
Adrenergic Uptake Inhibitors/chemistry , Indoles/chemistry , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacokinetics , Animals , Humans , Indoles/chemical synthesis , Indoles/pharmacokinetics , Models, Animal , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Rats , Serotonin Plasma Membrane Transport Proteins/chemistry , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter.
Subject(s)
Chemistry, Pharmaceutical/methods , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Norepinephrine/antagonists & inhibitors , Propanolamines/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacology , Animals , Dogs , Dopamine Plasma Membrane Transport Proteins/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Ligands , Models, Chemical , Propanolamines/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Neurotransmitter Uptake Inhibitors/chemical synthesis , Neurotransmitter Uptake Inhibitors/pharmacology , Norepinephrine/antagonists & inhibitors , Benzimidazoles/chemistry , Combinatorial Chemistry Techniques , Drug Design , Humans , Molecular Structure , Neurotransmitter Uptake Inhibitors/chemistry , Norepinephrine/metabolism , StereoisomerismABSTRACT
Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters.
Subject(s)
Indoles/chemical synthesis , Indoles/pharmacology , Neurotransmitter Uptake Inhibitors/chemical synthesis , Neurotransmitter Uptake Inhibitors/pharmacology , Norepinephrine/antagonists & inhibitors , Humans , Indoles/chemistry , Molecular Structure , Neurotransmitter Uptake Inhibitors/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.
Subject(s)
Cyclohexanols/chemistry , Ethylamines/chemistry , Ethylamines/pharmacology , Norepinephrine/metabolism , Symporters/antagonists & inhibitors , Animals , Cell Line , Ethylamines/therapeutic use , Female , Humans , Male , Mice , Models, Molecular , Molecular Structure , Pain/drug therapy , Rats , Structure-Activity Relationship , Symporters/metabolismABSTRACT
The purpose of this study was to characterize a new chemical entity, desvenlafaxine succinate (DVS). DVS is a novel salt form of the isolated major active metabolite of venlafaxine. Competitive radioligand binding assays were performed using cells expressing either the human serotonin (5-HT) transporter (hSERT) or norepinephrine (NE) transporter (hNET) with K(i) values for DVS of 40.2 +/- 1.6 and 558.4 +/- 121.6 nM, respectively. DVS showed weak binding affinity (62% inhibition at 100 microM) at the human dopamine (DA) transporter. Inhibition of [3H]5-HT or [3H]NE uptake by DVS for the hSERT or hNET produced IC50 values of 47.3 +/- 19.4 and 531.3 +/- 113.0 nM, respectively. DVS (10 microM), examined at a large number of nontransporter targets, showed no significant activity. DVS (30 mg/kg orally) rapidly penetrated the male rat brain and hypothalamus. DVS (30 mg/kg orally) significantly increased extracellular NE levels compared with baseline in the male rat hypothalamus but had no effect on DA levels using microdialysis. To mimic chronic selective serotonin reuptake inhibitor treatment and to block the inhibitory 5-HT(1A) autoreceptors, a 5-HT(1A) antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclo hexanecarboxamide maleate salt (WAY-100635) (0.3 mg/kg s.c.), was administered with DVS (30 mg/kg orally). 5-HT increased 78% compared with baseline with no additional increase in NE or DA levels. In conclusion, DVS is a new 5-HT and NE reuptake inhibitor in vitro and in vivo that demonstrates good brain-to-plasma ratios, suggesting utility in a variety of central nervous system-related disorders.
Subject(s)
Adrenergic Uptake Inhibitors/pharmacology , Cyclohexanols/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Adrenergic Uptake Inhibitors/metabolism , Adrenergic Uptake Inhibitors/pharmacokinetics , Animals , Brain/metabolism , Brain Chemistry/drug effects , Cell Line , Cell Membrane/drug effects , Cell Membrane/metabolism , Cyclohexanols/metabolism , Cyclohexanols/pharmacokinetics , Desvenlafaxine Succinate , Dopamine Plasma Membrane Transport Proteins/metabolism , Humans , Hypothalamus/metabolism , Male , Microdialysis , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Protein Binding , Radioligand Assay , Rats , Rats, Sprague-Dawley , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacokineticsABSTRACT
Progesterone (P4) is an essential reproductive steroid hormone required for many aspects of female reproductive physiology. Progestins are compounds that demonstrate progesterone-like activity and are used in oral contraception, hormone therapy, and treatment of some reproductive disorders, but differ widely in their chemical structures, potency, and pharmacokinetics. While numerous studies have assessed progestins on specific endpoints, little is known about the activation of global gene expression by progestins. We used Affymetrix GeneChip U133A expression arrays to examine the action of P4 and six clinically relevant synthetic progestins (3-ketodesogestrel, drospirenone, levonorgestrel, medroxyprogesterone acetate, norethindrone acetate, and trimegestone) on the progesterone receptor (PR)-positive T47Dco and the PR-negative T47D-Y breast cancer cell lines. Excluding drospirenone, one or more of the progestins-regulated 329 genes, with 30 genes regulated by at least 2.0-fold by all progestins in the T47Dco cells. The synthetic progestins show a high degree of similarity in their transcriptional responses, and each progestin regulates between 77 and 91% of the genes regulated by P4. Independent quantitative RT-PCR analysis confirmed a similar regulation for S100P, PPL, IL20RA, NET1, ATP1A1, HIG2, and CXCL12 (SDF-1) by all seven progestins. Attempts to find differentially regulated genes by any progestin compared to all other treatments failed, suggesting any differences are quantitative, not qualitative. This analysis demonstrates a high degree of similarity among these progestins on PR-regulated gene expression in T47D cells, suggesting a similar and fairly specific mode of action.
