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Structure of 1-(3-Aminopropyl)piperidine
CAS No.: 3529-08-6
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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
*For Research Use Only !
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Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing
Li, Bowen ; Manan, Rajith Singh ; Liang, Shun-Qing ; Gordon, Akiva ; Jiang, Allen ; Varley, Andrew , et al.
Abstract: The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for mRNA and CRISPR-Cas9 gene editors. Lead lipid nanoparticles are amenable for repeated intratracheal dosing and could achieve efficient gene editing in lung epithelium, providing avenues for gene therapy of congenital lung diseases.
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Purchased from AmBeed: 14916-80-4 ; 294-90-6 ; 13093-04-4 ; 65604-89-9 ; 22366-98-9 ; 143-28-2 ; 1484-84-0 ; 112-92-5 ; 3433-37-2 ; 34803-66-2 ; 622-26-4 ; 934-98-5 ; 3529-08-6 ; 123-70-6 ; 23356-96-9 ; 534-26-9 ; 20739-58-6 ; 4730-54-5 ; 108-00-9 ; 51388-00-2 ; 6711-48-4 ; 7209-38-3 ; 506-43-4 ; 2038-03-1 ; 142-25-6 ; 27578-60-5 ; 105-83-9 ; 67980-77-2 ; 877-96-3 ; 14712-23-3 ; 4572-03-6 ; 14156-95-7 ; 10563-26-5 ; 4097-88-5 ; 111-33-1 ; 123-12-6 ; 6261-22-9 ; 496808-04-9 ; 3644-18-6 ; 764-60-3 ; 1002-36-4 ; 51-45-6 ; 112086-54-1 ; 22104-79-6 ; 67529-83-3 ; 10563-29-8 ; 294-90-6 ; 506-43-4 ; 13901-38-7 ; 938459-02-0 ; 51721-39-2 ; 18128-28-4 ; 915922-79-1 ; 205059-32-1 ; 5298-72-6 ; 22763-69-5
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Rhym, Luke Hyunsik ;
Abstract: mRNA lipid nanoparticles (LNP) present a promising class of therapeutics, with broad applications in protein replacement therapy, gene editing, immunotherapy, and vaccines, owing to their versatility and precise nature. While recent years have seen dramatic improvements in the safety and efficacy of mRNA therapeutics, their functional delivery to target tissues and cells in vivo remains challenging, partly due to the lack of predictive power of in vitro assays and the low-throughput and costly nature of in vivo screening approaches. Thus, there is still a need for safe, specific, and potent mRNA delivery materials, as well as higher throughput in vivo screening methods. In this work, we developed a novel in vivo nanoparticle screening platform that relies on LC-MS/MS based detection of peptide barcodes translated from barcoded mRNAs in transfected cells, allowing for a readout of functional delivery that is directly proportional to protein production effected by each nanoparticle within a pooled library. We showed that this approach has high sensitivity and accuracy in both cultured cells in vitro and in tissues in vivo and demonstrated the applicability of this approach to in vivo screening of LNPs by developing and optimizing the formulation of a biodegradable LNP, RM133-3-21, for potent mRNA delivery to the liver. We then screened a large library of ionizable lipids for their ability to deliver mRNA to the lung and optimized both the structure and formulation of the lead compound. The resulting LNP, C15-21, is highly potent and is able to transfect up to 80% of lung endothelial cells after a single dose. In addition, we demonstrated that C15-21 is able to efficiently deliver Cas9 mRNA and sgRNA for targeted gene disruption in the lung, resulting in up to 7.5% gene editing in lung endothelial cells. Finally, we also developed materials and formulations that show high specificity for splenocytes in vivo. Taken together, the work presented in this thesis contributes to the field of mRNA therapeutics by increasing the throughput of LNP testing in vivo and by introducing novel delivery materials.
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CAS No. : | 3529-08-6 |
Formula : | C8H18N2 |
M.W : | 142.24 |
SMILES Code : | NCCCN1CCCCC1 |
MDL No. : | MFCD00023784 |
InChI Key : | JMUCXULQKPWSTJ-UHFFFAOYSA-N |
Pubchem ID : | 19049 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302-H314 |
Precautionary Statements: | P261-P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 2735 |
Packing Group: | Ⅲ |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 47.97 |
TPSA ? Topological Polar Surface Area: Calculated from |
29.26 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.09 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.53 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.44 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.9 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.14 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.02 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.86 |
Solubility | 19.7 mg/ml ; 0.139 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.72 |
Solubility | 27.4 mg/ml ; 0.192 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.43 |
Solubility | 5.24 mg/ml ; 0.0368 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
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 |
-6.79 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 |
1.0 |
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 |
0.0 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) |
1.25 |
* 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 |
---|---|---|
42.0% | Example 2 [Bis(3-piperidinopropylamino)methylene]malononitrile (Compound 2) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (300 mg, 1.76 mmol) was dissolved in THF (4 mL) and a solution of 3-piperidinopropylamine (251 mg, 1.76 mmol) in THF (1 mL) was added thereto. After stirring the mixture at room temperature for 2 hours, the mixture was added with a solution of 3-piperidinopropylamine (251 mg, 1.76 mmol) in THF (1 mL) and stirred at room temperature for 16 hours. Then, a solution of 3-piperidinopropylamine (75.2 mg, 0.529 mmol) in THF (0.5mL) was added thereto, followed by stirring at room temperature for 1.5 hours, and further stirring at 30C for 5 hours. After cooling, the mixture was added with water and the pH of the mixture was adjusted to 5 with 2 mol/L hydrochloric acid. Then, the pH of the mixture was adjusted to 9 with saturated aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and triturated with diisopropylether, followed by recrystallizing from n-hexane/ethyl acetate to obtain the titled compound (266 mg, 42.0%) as a white solid. 1H NMR (CDCl3, δppm): 1.44-1.50 (m, 4H), 1.57-1.64 (m, 8H), 1.71-1.80 (m, 4H), 2.39-2.45 (m, 12H), 3.43 (dd, J = 5.7, 11.0 Hz, 4H), 7.41 (brs, 2H). Melting point: 110-112C. |