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1.
J Med Chem ; 54(19): 6824-31, 2011 Oct 13.
Article in English | MEDLINE | ID: mdl-21916421

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/pharmacology
2.
Bioorg Med Chem Lett ; 20(12): 3742-5, 2010 Jun 15.
Article in English | MEDLINE | ID: mdl-20471258

ABSTRACT

A series of biaryl amides containing an azabicyclooctane amine headpiece were synthesized and evaluated as mixed arginine vasopressin (AVP) receptor antagonists. Several analogues, including 8g, 12g, 13d, and 13g, were shown to have excellent V(1a)- and good V(2)-receptor binding affinities. Compound 13d was further profiled for drug-like properties and for an in vitro comparison with conivaptan, the program's mixed V(1a)/V(2)-receptor antagonist standard.


Subject(s)
Antidiuretic Hormone Receptor Antagonists , Arginine Vasopressin/antagonists & inhibitors , Aza Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Octanes/chemical synthesis , Animals , Aza Compounds/pharmacology , Benzazepines , Bridged Bicyclo Compounds/pharmacology , Humans , Molecular Structure , Octanes/pharmacology , Structure-Activity Relationship
3.
J Med Chem ; 53(11): 4511-21, 2010 Jun 10.
Article in English | MEDLINE | ID: mdl-20462211

ABSTRACT

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/pharmacokinetics
4.
J Med Chem ; 53(5): 2051-62, 2010 Mar 11.
Article in English | MEDLINE | ID: mdl-20131864

ABSTRACT

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 Relationship
5.
Bioorg Med Chem Lett ; 20(5): 1555-8, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20153188

ABSTRACT

Two related series of selective norepinephrine reuptake inhibitors were synthesized based on 3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide or 3,4-dihydrosulfostyril cores, and screened for monoamine reuptake inhibition. Structure-activity relationships were determined for the series' in vitro potency and selectivity versus serotonin or dopamine transporter inhibition, and analogs based on both cores were identified as potent and selective NRIs. The 3,4-dihydrosulfostyril series was further tested for microsome stability, and compound 16j, which was optimized for both potency and stability, showed efficacy in an in vivo model of thermoregulatory dysfunction.


Subject(s)
Adrenergic Uptake Inhibitors/chemistry , Benzothiadiazines/chemistry , Cyclic S-Oxides/chemistry , Norepinephrine Plasma Membrane Transport Proteins/chemistry , Norepinephrine/metabolism , Thiazines/chemistry , Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacology , Animals , Biological Transport , Cyclic S-Oxides/chemical synthesis , Cyclic S-Oxides/pharmacology , Humans , Microsomes, Liver/metabolism , Models, Animal , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Rats , Structure-Activity Relationship , Thiazines/chemical synthesis , Thiazines/pharmacology
6.
ACS Med Chem Lett ; 1(3): 91-5, 2010 Jun 10.
Article in English | MEDLINE | ID: mdl-24900182

ABSTRACT

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.

7.
Bioorg Med Chem ; 18(1): 190-201, 2010 Jan 01.
Article in English | MEDLINE | ID: mdl-19932972

ABSTRACT

Piperidinyl diphenylsulfonyl sulfonamides are a novel class of molecules that have inhibitory binding affinity for sFRP-1. As a secreted protein sFRP-1 inhibits the function of the secreted Wnt glycoprotein. Therefore, as inhibitors of sFRP-1 these small molecules facilitate the Wnt/beta-catenin canonical signaling pathway. Details of the structure-activity relationships and biological activity of this structural class of compounds will be discussed.


Subject(s)
Glycoproteins/antagonists & inhibitors , Signal Transduction/drug effects , Sulfonamides/chemistry , Sulfonamides/pharmacology , Wnt Proteins/metabolism , Animals , Cell Line, Tumor , Glycoproteins/metabolism , Humans , Intracellular Signaling Peptides and Proteins , Mice , Microsomes, Liver/metabolism , Organ Culture Techniques , Osteogenesis/drug effects , Rats , Skull/cytology , Skull/drug effects , Structure-Activity Relationship , beta Catenin/metabolism
9.
J Med Chem ; 52(18): 5703-11, 2009 Sep 24.
Article in English | MEDLINE | ID: mdl-19722525

ABSTRACT

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 Specificity
10.
Bioorg Med Chem Lett ; 19(19): 5807-10, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19713106

ABSTRACT

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 Relationship
11.
Bioorg Med Chem Lett ; 19(17): 5029-32, 2009 Sep 01.
Article in English | MEDLINE | ID: mdl-19632110

ABSTRACT

A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (2R,3S)-isomer to be a potent norepinephrine reuptake inhibitor (IC(50)=28 nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter.


Subject(s)
Adrenergic Uptake Inhibitors/chemistry , Antidepressive Agents/chemistry , Norepinephrine/antagonists & inhibitors , Propanols/chemistry , Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacology , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacology , CHO Cells , Cell Line , Cricetinae , Cricetulus , Crystallography, X-Ray , Dogs , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Plasma Membrane Transport Proteins/metabolism , Drug Discovery , Humans , Molecular Conformation , Propanols/chemical synthesis , Propanols/pharmacology , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Structure-Activity Relationship
12.
Bone ; 44(6): 1063-8, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19254787

ABSTRACT

Canonical Wnt signaling has been demonstrated to increase bone formation, and Wnt pathway components are being pursued as potential drug targets for osteoporosis and other metabolic bone diseases. Deletion of the Wnt antagonist secreted frizzled-related protein (sFRP)-1 in mice activates canonical signaling in bone and increases trabecular bone formation in aged animals. We have developed small molecules that bind to and inhibit sFRP-1 in vitro and demonstrate robust anabolic activity in an ex vivo organ culture assay. A library of over 440,000 drug-like compounds was screened for inhibitors of human sFRP-1 using a cell-based functional assay that measured activation of canonical Wnt signaling with an optimized T-cell factor (TCF)-luciferase reporter gene assay. One of the hits in this screen, a diarylsulfone sulfonamide, bound to sFRP-1 with a K(D) of 0.35 microM in a tryptophan fluorescence quenching assay. This compound also selectively inhibited sFRP-1 with an EC(50) of 3.9 microM in the cell-based functional assay. Optimization of this high throughput screening hit for binding and functional potency as well as metabolic stability and other pharmaceutical properties led to improved lead compounds. One of these leads (WAY-316606) bound to sFRP-1 with a K(D) of 0.08 microM and inhibited it with an EC(50) of 0.65 microM. Moreover, this compound increased total bone area in a murine calvarial organ culture assay at concentrations as low as 0.0001 microM. This work demonstrates the feasibility of developing small molecules that inhibit sFRP-1 and stimulate canonical Wnt signaling to increase bone formation.


Subject(s)
Osteogenesis/drug effects , Proteins/antagonists & inhibitors , Sulfonamides/pharmacology , Wnt Proteins/antagonists & inhibitors , Animals , Apoptosis/drug effects , Cell Line, Tumor , Humans , Intracellular Signaling Peptides and Proteins , Mice , Organ Culture Techniques , Osteoblasts/cytology , Osteoblasts/drug effects , Osteocytes/cytology , Osteocytes/drug effects , Proteins/genetics , Proteins/metabolism , Skull/cytology , Skull/drug effects , Spectrometry, Fluorescence , Sulfonamides/chemistry
14.
J Med Chem ; 52(1): 105-16, 2009 Jan 08.
Article in English | MEDLINE | ID: mdl-19072540

ABSTRACT

The diphenylsulfonyl sulfonamide scaffold represented by 1 (WAY-316606) are small molecule inhibitors of the secreted protein sFRP-1, an endogenous antagonist of the secreted glycoprotein Wnt. Modulators of the Wnt pathway have been proposed as anabolic agents for the treatment of osteoporosis or other bone-related disorders. Details of the structure-activity relationships and biological activity from the first structural class of this scaffold will be discussed.


Subject(s)
Piperidines/chemistry , Proteins/antagonists & inhibitors , Proteins/metabolism , Signal Transduction/drug effects , Sulfanilamides/chemical synthesis , Sulfanilamides/pharmacology , Wnt Proteins/metabolism , Animals , Cell Line, Tumor , Genes, Reporter/genetics , Humans , Inhibitory Concentration 50 , Intracellular Signaling Peptides and Proteins , Isomerism , Mice , Molecular Structure , Protein Binding , Skull/drug effects , Structure-Activity Relationship , Sulfanilamides/chemistry , Wnt Proteins/genetics
15.
Bioorg Med Chem Lett ; 18(18): 4929-31, 2008 Sep 15.
Article in English | MEDLINE | ID: mdl-18771916

ABSTRACT

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 Relationship
16.
J Med Chem ; 51(13): 4038-49, 2008 Jul 10.
Article in English | MEDLINE | ID: mdl-18557608

ABSTRACT

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/metabolism
17.
Bioorg Med Chem Lett ; 17(21): 5796-800, 2007 Nov 01.
Article in English | MEDLINE | ID: mdl-17855087

ABSTRACT

Small molecule agonists and antagonists of the V(2)-vasopressin receptor have been discovered and have undergone clinical trials. In conjunction with these discovery programs, the synthesis and biological testing of various metabolites associated with these clinical targets were actively pursued. We now report the results of our synthetic efforts and the corresponding biological data generated for several of the metabolites of WAY-151932 and CL-347985 (Lixivaptan).


Subject(s)
Antidiuretic Hormone Receptor Antagonists , Azepines/chemistry , Benzamides/chemistry , Benzazepines/chemistry , Receptors, Vasopressin/agonists , Azepines/chemical synthesis , Azepines/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Benzazepines/chemical synthesis , Benzazepines/pharmacology , Humans , In Vitro Techniques , Pyrroles
18.
Bioorg Med Chem ; 14(24): 8455-66, 2006 Dec 15.
Article in English | MEDLINE | ID: mdl-16973367

ABSTRACT

Compounds with a combination of norepinephrine and serotonin reuptake inhibition have been approved in the US and Europe for a number of indications, including major depressive disorder and pain disorders such as diabetic neuropathy and fibromyalgia. Efforts to design selective norepinephrine reuptake inhibitors based on SAR from the aryloxypropanamine series of monoamine reuptake inhibitors have led to the identification of a potent new class of dual acting norepinephrine and serotonin reuptake inhibitors, namely the 3-(1H-indol-1-yl)-3-arylpropan-1-amines.


Subject(s)
Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacology , Biogenic Amines/chemical synthesis , Indoles/chemical synthesis , Indoles/pharmacology , Norepinephrine/antagonists & inhibitors , Propylamines/chemical synthesis , Propylamines/pharmacology , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/chemistry , Biogenic Amines/pharmacology , Cell Line, Tumor/drug effects , Choriocarcinoma/drug therapy , Choriocarcinoma/pathology , Dopamine Plasma Membrane Transport Proteins/metabolism , Humans , Placenta/drug effects , Placenta/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Structure-Activity Relationship
19.
Bioorg Med Chem ; 14(10): 3455-66, 2006 May 15.
Article in English | MEDLINE | ID: mdl-16427291

ABSTRACT

The anti-inflammatory activity of non-selective estrogens has been attributed to their ability to antagonize the activity of nuclear factor kappaB (NF-kappaB), a known mediator of inflammatory responses. Here we report the identification of a potent new class of pathway-selective ER ligands that selectively antagonize NF-kappaB functional activity, while exhibiting a lack of classical estrogenic effect.


Subject(s)
Quinoxalines/chemical synthesis , Receptors, Estrogen/metabolism , Cells, Cultured , Drug Evaluation, Preclinical , Humans , Ligands , Molecular Structure , NF-kappa B/antagonists & inhibitors , NF-kappa B/drug effects , Quinoxalines/chemistry , Quinoxalines/pharmacology , Receptors, Estrogen/drug effects , Signal Transduction/drug effects
20.
Bioorg Med Chem Lett ; 16(4): 954-9, 2006 Feb 15.
Article in English | MEDLINE | ID: mdl-16297621

ABSTRACT

Our efforts in seeking low molecular weight agonists of the antidiuretic peptide hormone arginine vasopressin (AVP) have led to the identification of the clinical candidate WAY-151932 (VNA-932). Further exploration of the structural requirements for agonist activity has provided another class of potent, orally active, non-peptidic vasopressin V2 receptor selective agonists exemplified by the 5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepine as a candidate for further development.


Subject(s)
Benzodiazepines/classification , Benzodiazepines/pharmacology , Receptors, Vasopressin/agonists , Administration, Oral , Animals , Benzazepines/administration & dosage , Benzodiazepines/administration & dosage , Drug Evaluation, Preclinical , Molecular Structure , Molecular Weight , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
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