| Size | Price | Stock | Qty |
|---|---|---|---|
| 50mg |
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| Other Sizes |
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| Targets |
Anti-bacterial
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|---|---|
| ln Vitro |
SQ609 is toxic to Mtb-infected macrophages and, at 4μg/ml, inhibits more than 90% of intracellular bacterial growth[1].
|
| ln Vivo |
In Mtb-infected rats, SQ609 (10 mg/kg; intravenous injection) totally stops weight loss and extends the therapeutic benefit for an additional 10–15 days after drug withdrawal[1].
|
| Enzyme Assay |
MIC determination. [1]
An aliquot of a frozen stock of M. tuberculosis H37Rv (ATCC 25618) was thawed and grown in Middlebrook 7H9 (Difco) supplemented with bovine serum albumin (BSA), dextrose, and catalase to an O.D.600 of 0.2 at 37C with 5% CO2. Experimental (hits) and control (INH, EMB) drug compounds were serially diluted from 50 to 0.39µM. Each well was inoculated with a 1:100 dilution of the H37Rv culture. MIC99 for each compound was determined after 10-14 days of incubation at 37C with 5% CO2. Determination of intracellular activity against MTB [1] J774A.1 mouse macrophage (MΦ) cell line (ATCC TIB-67) was used to investigate intracellular activities of the drugs. MΦ were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (FBS) in 24-well tissue culture plates at 106 cells/ml/well and incubated at 37°C in a CO2 incubator for 3 hr. Cells were washed 2x with Hanks’ Balanced Salt Solution (HBSS) and infected with Mtb suspension. For MΦ infection, log phase culture of Mtb-pSMT1 strain was washed twice with DMEM, sonicated for 10 sec, adjusted to 0.1 OD at λ600 and diluted 1/20 in DMEM. After 3 hr incubation with MTB, MΦ were washed 3x with HBSS and incubated with DMEM containing drugs (test) or DMEM alone (controls). Mtb-infected MΦ were incubated with drugs for 4 days and then culture medium was replaced with drug-free DMEM and cultures were incubated for 3 more days. On day 0 and day 7, MΦ in triplicate wells were lysed with 0.1 % Triton X-100 and the relative light units (RLU) of the lysates were counted in a luminometer. |
| Animal Protocol |
Animal/Disease Models: TB susceptible mice (C3H/He)[1]
Doses: 10 mg/kg Route of Administration: Iv Experimental Results: Prevented weight loss in the Mtb-infected animals and prolonged the therapeutic effect following drug withdrawal for another 10 -15 days. In vivo rapid screening. [1] TB susceptible mice of C3H/HeNCrlBR (C3H) inbred strain (average weight, 22 g) were allowed to acclimate for 1 week. At the initiation of the experiment, all mice were weighed, and their weights were recorded. We used portable electronic balance NO4120 for measurement of small-laboratory-animal body weight. Mice were inoculated i.v. in the tail vein with 0.2 ml of bacterial suspension containing approximately 106 CFU of M. tuberculosis H37Rv in PBS with 0.05% Tween 80. At 7 days, the treatment of infected mice with drugs was initiated. Mice were treated daily with tested compounds. Two control groups, one of infected mice and one of uninfected mice, received water (placebo control). INH served as standard TB drug (positive drug control). The dynamics of body weight gain (or loss) of mice was monitored daily, and drug (or placebo) treatment was continued until day 20. |
| References |
[1] Identification of SQ609 as a lead compound from a library of dipiperidines. Bioorg Med Chem Lett. 2011;21(18):5353-5357.
|
| Additional Infomation |
In summary, we thoroughly analyzed the SAR of dipiperidine compound series and evaluated leads in in vitro and in vivo assays. Based on the in vivo data, SQ609 was identified as the best in class compound and will be further investigated for its antitubercular activity. [1]
We recently reported that compounds created around a dipiperidine scaffold demonstrated activity against Mycobacterium tuberculosis (Mtb) (Bogatcheva, E.; Hanrahan, C.; Chen, P.; Gearhart, J.; Sacksteder, K.; Einck, L.; Nacy, C.; Protopopova, M. Bioorg. Med. Chem. Lett.2010, 20, 201). To optimize the dipiperidine compound series and to select a lead compound to advance into preclinical studies, we evaluated the structure-activity relationship (SAR) of our proprietary libraries. The (piperidin-4-ylmethyl)piperidine scaffold was an essential structural element required for antibacterial activity. Based on SAR, we synthesized a focused library of 313 new dipiperidines to delineate additional structural features responsible for antitubercular activity. Thirty new active compounds with MIC 10-20 μg/ml on Mtb were identified, but none was better than the original hits of this series, SQ609, SQ614, and SQ615. In Mtb-infected macrophages in vitro, SQ609 and SQ614 inhibited more than 90% of intracellular bacterial growth at 4 μg/ml; SQ615 was toxic to these cells. In mice infected with Mtb, weight loss was completely prevented by SQ609, but not SQ614, and SQ609 had a prolonged therapeutic effect, extended by 10-15 days, after cessation of therapy. Based on in vitro and in vivo antitubercular activity, SQ609 was identified as the best-in-class dipiperidine compound in the series.[1] |
| Molecular Formula |
C22H38N2O
|
|---|---|
| Molecular Weight |
346.549926280975
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| Exact Mass |
346.298
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| Elemental Analysis |
C, 76.25; H, 11.05; N, 8.08; O, 4.62
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| CAS # |
627052-25-9
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| PubChem CID |
9841182
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| Appearance |
Typically exists as White to off-white solid at room temperature
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| LogP |
3.8
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| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
3
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
25
|
| Complexity |
421
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
OC1CCN(CC1)CC1CCN(CC1)CC12CC3CC(CC(C3)C1)C2
|
| InChi Key |
YUBKDPOCUHUSLW-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C22H38N2O/c25-21-3-7-23(8-4-21)15-17-1-5-24(6-2-17)16-22-12-18-9-19(13-22)11-20(10-18)14-22/h17-21,25H,1-16H2
|
| Chemical Name |
1-[[1-(1-adamantylmethyl)piperidin-4-yl]methyl]piperidin-4-ol
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| Synonyms |
SQ609; SQ-609; 627052-25-9; C9PLJ41X6M; 1-((1-(1-Adamantylmethyl)piperidin-4-yl)methyl)piperidin-4-ol; 4-Piperidinol, 1-((1-(tricyclo(3.3.1.13,7)dec-1-ylmethyl)-4-piperidinyl)methyl)-; 1-[[1-(1-adamantylmethyl)piperidin-4-yl]methyl]piperidin-4-ol; SQ609 cpd;
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : 6.67 mg/mL (19.25 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.67 mg/mL (1.93 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 0.67 mg/mL (1.93 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8856 mL | 14.4279 mL | 28.8559 mL | |
| 5 mM | 0.5771 mL | 2.8856 mL | 5.7712 mL | |
| 10 mM | 0.2886 mL | 1.4428 mL | 2.8856 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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