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Structure-Based Drug Design of ADRA2A Antagonists Derived from Yohimbine
Artem Chayka ; Michal Česnek ; Erika Kužmová , et al. JMC,2024,67(12):10135-10151. DOI: 10.1021/acs.jmedchem.4c00323 PubMed ID: 38857067
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Abstract: Yohimbine, a natural indole alkaloid and a nonselective adrenoceptor antagonist, possesses potential benefits in treating inflammatory disorders and sepsis. Nevertheless, its broader clinical use faces challenges due to its low receptor selectivity. A structure–activity relationship study of novel yohimbine analogues identified amino esters of yohimbic acid as potent and selective ADRA2A antagonists. Specifically, amino ester 4n, in comparison to yohimbine, showed a 6-fold higher ADRA1A/ADRA2A selectivity index (SI > 556 for 4n) and a 25-fold higher ADRA2B/ADRA2A selectivity index. Compound 4n also demonstrated high plasma and microsomal stability, moderate-to-low membrane permeability determining its limited ability to cross the blood–brain barrier, and negligible toxicity on nontumor normal human dermal fibroblasts. Compound 4n represents an important complementary pharmacological tool to study the involvement of adrenoceptor subtypes in pathophysiologic conditions such as inflammation and sepsis and a novel candidate for further preclinical development to treat ADRA2A-mediated pathologies.
Purchased from AmBeed: 25952-53-8 ; 36805-97-7 ; 6674-22-2
CAS No. : | 25952-53-8 | MDL No. : | MFCD00012503 |
Formula : | C8H18ClN3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FPQQSJJWHUJYPU-UHFFFAOYSA-N |
M.W : | 191.70 | Pubchem ID : | 2723939 |
Synonyms : |
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Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P260-P264-P270-P272-P273-P280-P301+P312+P330-P302+P352+P312-P314-P333+P313-P391-P405-P501 | UN#: | 2811 |
Hazard Statements: | H302-H311-H315-H317-H373-H410 | Packing Group: | Ⅲ |
GHS Pictogram: |
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* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In pyridine; ethyl acetate; | (1) Carbazic acid tert-butyl ester (9.21 g) was dissolved in pyridine (120 ml), followed by addition of <strong>[29006-02-8]4-methoxybutyric acid</strong> (9.06 g) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride salt (20.0 g), and stirred at ambient temperature for 64 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, which was then washed with aqueous 1 mol/liter hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, N'-(4-methoxybutyryl) hydrazine carboxylic acid tert-butyl ester was obtained in yellow oil (9.30 g, 57%). The physico-chemical values are as follows. 1H-NMR (DMSO-d6) delta: 1.39 (9H, s), 1.65-1.78 (2H, m), 2.07-2.12 (2H, m), 3.21 (3H, s), 3.30-3.34 (2H, m), 8.64 (1H, s), 9.46 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; In dichioromethane; | (1) 2-Amino-4-[1-(3,4-dibenzyloxybenzoyl)-4-piperidinyl]-6-(4-methoxyphenylmethyl) pyrimidine STR73 To a solution of 2-amino-4-(4-methoxyphenylmethyl)-6-(4-piperidinyl)pyrimidine (160 mg, 0.54 mmol), <strong>[1570-05-4]3,4-dibenzyloxybenzoic acid</strong> (179 mg, 0.54 mmol) and 1-hydroxybenzotriazole (72 mg, 0.54 mmol) in dichioromethane (150 ml) were added 1-ethyl-3-(N, N'-dimethylaminopropyl)carbodiimide hydrochloride (103 mg, 0.54 mmol) at room temperature under nitrogen atmosphere. After stirring for about 30 minutes, the mixture was washed successively with saturated sodium hydrogen carbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and then evaporated. The residue was purified by column chromatography (chloroform:methanol=99:1) to give the titled compound (477 mg). 1 H-NMR (CDCl3): delta 1.77 (4H, m), 2.59 (1H, m), 2.84 (2H, m), 3.78 (3H, s), 3.82 (2H, s), 3.90 (1H, m), 4.70 (1H, m), 5.11 (2H, s), 5.17 (2H, s), 5.18 (2H,s), 6.24 (1H, s), 6.84-7.00 (5H, m), 7.14-7.44 (12H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride; In chloroform; acetonitrile; | 1) Synthesis of N-[3-(1-tert-butoxycarbonyl-4-piperidyl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide In acetonitrile (120 ml) was suspended 6.55 g (30.0 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid as well as 6.91 g (60.0 mM) of N-hydroxysuccinimide, followed by additino of 11.50 g (60.0 mM) of N-ethyl-N'-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride, and the mixture was stirred at room temperature for 1 hour. The solvent was then distilled off under reduced pressure and the residue was extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4 and the solvent was distilled off under reduced pressure to provide the active ester. To a solution of this active ester in chloroform (100 ml) was added 8.4 ml (60.0 mM) m of triethylamine as well as 8.72 g (36.0 mM) of 3-(1-tert-butoxycarbonyl-4-piperidyl)propylamine and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was washed with purified water and the organic layer was further washed with saturated m aqueous solution of sodium chloride. After the organic layer was dried over MgSO4, the solvent was distilled off under reduced pressure and the residue was purified by column chromatography (ethyl acetate/ethanol=10/1) to provide the title compound. Red solid. Yield 10.16 g (76%) 1H-NMR (200 MHz, CDCl3) delta: 0.95-1.41 (m, 4H), 1.45 (s, 9H), 1.48-1.72 (m, 5H), 2.61-2.73 (m, 2H), 3.28 (m, 2H), 4.05-4.14 (m, 2H), 5.79 (dd, J=2.2, 5.8 Hz, 1H), 6.02 (t, J=5.6 Hz, 1H), 6.63-6.70 (m, 3H), 7.02 (s, 1H). IR (KBr): 1684, 1624, 1278, 1161 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethanolamine; In n-heptane; dichloromethane; | Step 1: 5-Chloro-3-fluoro-N-methoxy-N-methylpicolinamide To a stirred mixture of <strong>[207994-08-9]5-chloro-3-fluoropicolinic acid</strong> (3.62 g, 20.62 mmol) in dichloromethane (50 mL) were added 1H-benzo[d][1,2,3]triazol-1-ol (0.42 g, 3.09 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine HCl (5.93 g, 30.9 mmol), N,O-dimethylhydroxylamine HCl (3.02 g, 30.9 mmol), and TEA (7.19 mL, 51.6 mmol). The reaction mixture was stirred at RT for 2 hours, and then partitioned between ethyl acetate and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography, eluting with 0-100% EtOAc in heptane, to provide the title intermediate (3.71 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | A) tert-butyl (cyclopropylmethyl)(trans-2-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}cyclopropyl)carbamate A solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (75 mg) in DMF (3 mL) was ice-cooled, and <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (33.4 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (143 mg), 1-hydroxybenzotriazole (49.4 mg) and diisopropylethylamine (80 mg) were added. The mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (72 mg). MS (API+): [M-tBu+2H]+ 341.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; In N,N-dimethyl-formamide; | A) tert-butyl [trans-2-(4-[4-(benzoylamino)benzoyl]amino}-phenyl)cyclopropyl](cyclopropylmethyl)carbamate To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (90.9 mg), <strong>[582-80-9]4-benzamidobenzoic acid</strong> (87 mg) and 1-hydroxybenzotriazole (60.9 mg) in DMF (1.5 mL) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg). The reaction mixture was stirred at room temperature for 2 hr, and poured into 0.5N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate/diisopropyl ether to give the title compound (98.0 mg). 1H NMR (300 MHz, DMSO-d6) delta 0.07-0.17 (1H, m), 0.18-0.29 (1H, m), 0.34-0.52 (2H, m), 0.91-1.02 (1H, m), 1.15-1.28 (2H, m), 1.37 (9H, s), 2.01-2.12 (1H, m), 2.67-2.76 (1H, m), 3.00 (1H, dd, J = 14.5, 7.0 Hz), 3.20 (1H, dd, J = 14.5, 6.9 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.50-7.63 (3H, m), 7.67 (2H, d, J = 8.7 Hz), 7.91-8.01 (6H, m), 10.09 (1H, s), 10.51 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | 1-3. Synthesis of Low-Molecular-Weight Compound ID-52 (8a) Among the above-described low-molecular-weight compounds, ID-52 (3-(3-1H-indol-3-yl-acryloylamino)-benzoic acid methyl ester (8a)) was prepared in the following manner. Trans-3-indoleacrylic acid (7a, 150 mg, 0.8 mmol) and 3-amino-benzoic acid methyl ester (6a, 218 mg, 1.44 mmol) were dissolved in DMF, and 1-[3-(dimethyamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 230 mg, 1.2 mmol), hydroxy-7-azabenotriazole (HOAT, 163 mg, 1.2 mmol) and N,N-diisopropylethylamine (DIPEA, 0.21 mL, 1.2 mmol) were added to the solution to cause a coupling reaction. The reaction solution was stirred overnight at room temperature. Then, the resulting material was separated and purified to obtain 3-(3-1H-indol-3-yl-acryloylamino)-benzoic acid methyl ester (ID-52) as a yellow solid. 1H NMR (CDCl3, 300 MHz) d=8.90 (s, 1H), 8.21 (s, 1H), 7.86-8.03 (m, 4H), 7.76 (d, J=8.1 Hz, 1H), 7.36-7.41 (m, 3H), 7.20 (m, 2H), 6.60 (d, J=15.3 Hz, 2H), 3.88 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; | Trifluoroacetic Acid/tert-butyl {(2S)-4-[{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl]-2,2-dimethylpropyl}(glycoloyl)amino]-1-hydrazino-1-oxobutan-2-yl}carbamate (1:1) 150 mg (0.16 mmol) of Intermediate C3 were dissolved in 21 ml of DMF, and then 37.2 mg (0.19 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), 37 mg (0.243 mmol) of 1-hydroxybenzotriazole, 85 mul of N,N-diisopropylethylamine and finally 45 mg (0.18 mmol) of commercially available 9H-fluoren-9-ylmethyl hydrazinecarboxylate were added. The mixture was stirred at RT overnight and then concentrated under reduced pressure. The residue was purified by preparative HPLC. The appropriate fractions were concentrated and the residue was lyophilized from acetonitrile/water. This gave 60 mg (41percent of theory) of the protected intermediate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In isopropyl alcohol; at 80℃; for 0.25h;Microwave irradiation; | General procedure: A mixture of o-phenylenediamine (1.0 mmol) and EDC.HCl (1.1 mmol) in 2-propanol (10 mL) was irradiated in microwave apparatus at 200 W (80 °C) for 15 min. The reaction was monitored by TLC (eluent CH2Cl2 / MeOH 95:5). After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure and the obtained crude product was purified by flash column chromatography using silica gel (100-200 mesh) with 1-5percent MeOH/CH2Cl2 as eluent. The fractions containing product were collected and concentrated under reduced pressure to afford N-ethyl-1Hbenzo[d]imidazol-2-amine (1a, 90percent yield) as an off white solid. |
A848717[ 7084-11-9 ]
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine xhydrochloride
Reason: