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Chemical Structure| 3529-08-6 Chemical Structure| 3529-08-6

Structure of 1-(3-Aminopropyl)piperidine
CAS No.: 3529-08-6

Chemical Structure| 3529-08-6

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Product Citations

Product Citations      Show More

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.

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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Alternative Products

Product Details of [ 3529-08-6 ]

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

Safety of [ 3529-08-6 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302-H314
Precautionary Statements:P261-P280-P305+P351+P338-P310
Class:8
UN#:2735
Packing Group:

Computational Chemistry of [ 3529-08-6 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

29.26 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.09
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.53
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

0.44
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.9
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.14
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.02

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-0.86
Solubility 19.7 mg/ml ; 0.139 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-0.72
Solubility 27.4 mg/ml ; 0.192 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-1.43
Solubility 5.24 mg/ml ; 0.0368 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.79 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.25

Application In Synthesis of [ 3529-08-6 ]

* 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.

  • Downstream synthetic route of [ 3529-08-6 ]

[ 3529-08-6 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 3529-08-6 ]
  • [ 33045-53-3 ]
  • [ 129010-92-0 ]
  • 2
  • [ 3529-08-6 ]
  • [ 3356-89-6 ]
  • [ 86684-07-3 ]
  • 3
  • [ 3529-08-6 ]
  • [ 5147-80-8 ]
  • [Bis(3-piperidinopropylamino)methylene]malononitrile [ No CAS ]
YieldReaction ConditionsOperation 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.
  • 4
  • [ 3529-08-6 ]
  • [ 120085-99-6 ]
  • 2,9-bis{4-[(3-piperidin-1-ylpropyl)iminomethyl]phenyl}-1,10-phenanthroline [ No CAS ]
 

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