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Structure of 2550-36-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
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Henderson, Ian M. ; Zeng, Fanxun ; Bhuiyan, Nazmul H. ; Luo, Dan ; Martinez, Maria ; Smoake, Jane , et al.
Abstract: Interest in development of potent, selective inhibitors of the phosphatase from the receptor type protein tyrosine phosphatase PTPRD as antiaddiction agents is supported by human genetics, mouse models and studies of our lead compound PTPRD phosphatase inhibitor, 7-butoxy illudalic acid analog 1 (7-BIA). We now report structure-activity relationships for almost 70 7-BIA-related compounds and results that nominate a 7- cyclopentyl methoxy analog as a candidate for further development. While efforts to design 7-BIA analogs with substitutions for other parts failed to yield potent inhibitors of PTPRDs phosphatase, ten 7-position substituted analogs displayed greater potency at PTPRD than 7-BIA. Several were more selective for PTPRD vs the receptor type protein tyrosine phosphatases S, F and J or the nonreceptor type protein tyrosine phosphatase N1 (PTPRS, PTPRF, PTPRJ or PTPN1/PTP1B), phosphatases at which 7-BIA displays activity. In silico studies aided design of novel analogs. A 7-position cyclopentyl methoxy substituted 7-BIA analog termed NHB1109 displayed 600-700 nM potencies in inhibiting PTPRD and PTPRS, improved selectivity vs PTPRS, PTPRF, PTPRJ or PTPN1/PTP1B phosphatases, no substantial potency at other protein tyrosine phosphatases screened, no significant potency at any of the targets of clin.-useful drugs identified in EUROFINS screens and significant oral bioavailability. Oral doses up to 200 mg/kg were well tolerated by mice, though higher doses resulted in reduced weight and apparent ileus without clear organ histopathol. NHB1109 provides a good candidate to advance to in vivo studies in addiction paradigms and toward human use to reduce reward from addictive substances.
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Keywords: Receptor type protein tyrosine phosphatase ; Cell adhesion molecule ; Addiction ; Drug reward ; Opiates ; Stimulants
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Purchased from AmBeed: 37595-74-7 ; 637-59-2 ; 103-63-9 ; 64473-35-4 ; 20443-99-6 ; 939-26-4 ; 3814-32-2 ; 3814-30-0 ; 36881-42-2 ; 17247-58-4 ; 589-15-1 ; 2550-36-9 ; 78358-86-8 ; 7051-34-5 ; 161043-38-5 ; 161395-96-6 ; 59311-24-9 ; 83642-03-9
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Janssens, Liesl K ; Ametovski, Adam ; Sparkes, Eric ; Boyd, Rochelle ; Lai, Felcia ; Maloney, Callan J , et al.
Abstract: Over 200 synthetic cannabinoid receptor agonists (SCRAs) have been identified as newpsychoactive substances. EffectivemonitoringandcharacterizationofSCRAsarehindered by the rapid pace of structural evolution. Ahead of possible appearanceontheillicitdrugmarket,newSCRAsweresynthesized tocompletea systematic libraryof cumyl-indole-(e.g.,CUMYL CPrMICA,CUMYL-CPMICA)andcumyl-indazole-carboxamides (e.g.,CUMYL-CPrMINACA,CUMYL-CPMINACA), encompass ing butyl, pentyl, cyclopropylmethyl, cyclobutylmethyl, cyclo pentylmethyl, andcyclohexylmethyl tails.Comprehensivepharma cologicalcharacterizationwasperformedwiththreeassayformats, monitoring the recruitment of either wild-type or C-terminally truncated(βarr2d366)β-arrestin2totheactivatedcannabinoid1 receptor(CB1)ormonitoringGβγ-mediatedmembranehyperpolarization.Alteredcompoundcharacterizationwasobservedwhen comparingderivedpotency(EC50)andefficacy(Emax)values frombothassaysmonitoringthesameoradifferentsignalingevent, whereasrangesandrankingordersweresimilar.Structure−activityrelationships(SAR)wereassessedinthreefold, resultinginthe identificationof thependant tailasacriticalpharmacophore,withtheoptimalchainlengthforCB1activationapproximatingann pentyl (e.g., cyclopentylmethyl or cyclohexylmethyl tail). The activityof the SCRAs encompassing cyclic tails decreasedwith decreasingnumberofcarbonsformingthecyclicmoiety,withCUMYL-CPrMICAshowingtheleastCB1activityinallassayformats. The SARs were rationalized viamolecular docking, demonstrating the importance of the optimal steric contributionof the hydrophobictail.WhileSARconclusionsremainedlargelyunchanged, thedifferential compoundcharacterizationbybothsimilar anddifferentassaydesignsemphasizestheimportanceofdetailingspecificassaycharacteristicstoallowadequateinterpretationof potenciesandefficacies.
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Keywords: structure−activity relationship ; functional assays ; membrane potential ; βarrestin2 recruitment ; new psychoactive substances ; molecular docking
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Purchased from AmBeed: 43120-28-1 ; 585-32-0 ; 3814-30-0 ; 120-72-9 ; 17247-58-4 ; 2550-36-9 ; 7051-34-5 ; 173600-10-7
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CAS No. : | 2550-36-9 |
Formula : | C7H13Br |
M.W : | 177.08 |
SMILES Code : | BrCC1CCCCC1 |
MDL No. : | MFCD00001509 |
InChI Key : | UUWSLBWDFJMSFP-UHFFFAOYSA-N |
Pubchem ID : | 137636 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H225 |
Precautionary Statements: | P210-P403+P235 |
Class: | 3 |
UN#: | 1993 |
Packing Group: | Ⅲ |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 41.52 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.45 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.36 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.96 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.06 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.0 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.97 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.99 |
Solubility | 0.182 mg/ml ; 0.00103 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.04 |
Solubility | 0.162 mg/ml ; 0.000916 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.57 |
Solubility | 0.476 mg/ml ; 0.00269 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-4.99 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.2 |
* 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 |
---|---|---|
74% | To a solution of commercially available l//-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (0.35 g, 2.0 mmol) and cyclohexylmethyl bromide (0.31 mL, 2.2 mmol) in DMF (2 mL) was added sodium hydride (92 mg, 2.3 mmol). After stirring at room temperature for 3 hr, the solution was diluted with water (25 mL) and ethyl acetate (75 mL), the organic layer was washed again with dilute NaHCO3 (25 mL) and then brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:24) to provide l-cyclohexylmethyl-l//-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> as a white solid (0.40 g, 74% yield). 1H NMR (400 MHz, DMSO) δ 8.10 (s, IH), 7.62 (m, 2H), 7.58 (d, IH, J = 3.1 Hz), 6.52 (d, IH, J= 3.1 Hz), 4.10 (d, 2H, J= IA Hz), 3.85 (s, 3H), 1.77 (m, IH), 1.65-1.57 (m 3H), 1.46 (m, 2H), 1.19 (m, 3H), 0.98 (m, 2H). | |
32% | With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 8h; | 1H-<strong>[50820-65-0]indole-6-carboxylic acid methyl ester</strong> (300mg, 1.71mmol) was dissolved in dimethyl formamide (7ml). Bromomethyl cyclohexane (0.5ml, 3.42mmol) and sodium hydride (150mg, 3.42mmol) were added dropwise thereto at 0, and then the mixture was stirred for 8 hours at room temperature. 1N hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (150mg, 32%). [611] NMR:1H-NMR(400HMz, CDCl3); δ 7.29-7.39 (m, 2H), 7.19 (d, 1H), 7.13 (m, 1H), 7.00-7.09 (m, 2H), 6.66 (m, 1H), 4.83 (s, 2H), 2.06 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With potassium carbonate; In acetonitrile; at 180℃; for 0.166667h;Microwave irradiation;Product distribution / selectivity; | EXAMPLE 9 : 1-(Cyclohexylmethyl)-<strong>[53242-51-6]5-(4-methoxyphenyl)pyridin-2(1H)-one</strong> (Final Compound 4-03)According to Scheme 5 Step 2: To a solution of 5-(4-methoxyphenyl)pyridin-2(lH)- one (leq, 0.35mmol, 70mg, Example 7 Step 1) in acetonitrile (2mL) were added K2CO3 (10eq, 3.50mmol, 0.48g) and (bromomethyl)cyclohexane (10eq, 3.50mmol, 0.49mL). The reaction was microwaved for 10 minutes at 180C. The reaction was allowed to cool. The reaction was then filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 15g SiO2) using CH2Cl2/AcOEt (80/20, Rf=0.3). The product was further purified by reverse phase C18 column using water/acetonitrile 60/40 to afford 1- (cyclohexylmethyl)-5-(4-methoxyphenyl)pyridin-2(lH)-one (0.11mmol, 32mg, 31%) as a colorless oil. LC (XTerra RP18, 3.5mum, 3.0x50mm Column): RT = 4.72min; MS m/z (CI) [MH]+= 298; 1H NMR (300MHz, CDCl3) delta 0.85-1.09 (m, 2H), 1.09-1.32 (m, 3H), 1.53-1.78 (m, 5H), 1.78-2.00 (m, 1H), 3.74 (d, J=7.3Hz, 2H), 3.77 (s, 3H), 6.57 (d, J=9.4Hz, 1H), 6.88 (d, J=8.7Hz, 2H), 7.29-7.35 (3H), 7.49 (dd, J=2.7Hz, 9.4Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | H181 (0.667mmol) was dissolved in DMF (lOmL) and cooled to 0°C with ice bath. To this solution under nitrogen were added in sequence sodium hydride (106mg, 2.67mmol, 4.0eq) and (bromomethyl)cyclohexane (0.372ml, 2.67mmol, 4.0eq). The reaction mixture was stirred for 18 hours then treated with 1M HC1 (10ml). After extraction with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous Na2S04. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound(109.2mg, 66percent yield). 1H NMR (300 MHz, DMSO-d6): delta 9.08 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.03 (dd, J = 8.4 2.7 Hz, 1H), 4.90 (m, 2H), 3.78 (d, J = 6.3 Hz, 2H) and 1.83-1.01 (m, l lH) ppm. Mp 126-127°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In methanol; | Example 115 6-[4-(cyclohexylmethylsulfonyl)-l-piperidyl]-l-methyl-5H-pyrazolo[3 4-d]pyrimidin-4- one (1-135) tert- utyl 4-mercapto-l-piperidinecarboxylate was alkylated with ( bromomethyl)cyclohexane (KOH, MeOH), oxidized to the sulfone (MCPBA) and deprotected by catalytic hydrogenolysis (Pd/C, H2, MeOH). Condensation of the resulting amine with Intermediate A affords the title compound: 1H-NMR (400MHz, DMSO-d6) δ ppm 10.96 (s, IH), 7.77 (s, IH), 4.48 (d, J=13.6Hz, 2H), 3.72(s, 3H), 3.45-3.32 (m, IH), 3.03-2.97 (m, 4H), 2.07 (d, J=l 1.6Hz, 2H), 1.97-1.84 (m, 3H), 1.67-1.55 (m, 5H), 1.33-1.20 (m, 2H), 1.20-1.02 (m, 3H) |
A135676 [941-37-7]
1-Bromo-3,5-dimethyladamantane
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