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Chemical Structure| 27578-60-5 Chemical Structure| 27578-60-5

Structure of 1-(2-Aminoethyl)piperidine
CAS No.: 27578-60-5

Chemical Structure| 27578-60-5

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Product Citations

Product Citations      Show More

Álvaro Peña ; Juan Heredero ; Beatriz Blandín ; Elena Mata ; Diego De Miguel ; Alfonso Toro , et al.

Abstract: Ionizable lipids are an essential component of lipid nanoparticles (LNPs) for an efficient mRNA delivery. However, optimizing their chemical structures for high protein expression, efficient endosomal escape, and selective organ targeting remains challenging due to complex structure-activity relationships and multistep synthesis. In this study, we introduce a rapid, high-throughput platform for screening ionizable lipids using a two-step, scalable synthesis involving a one-pot 3-component click-like reaction. This method, herein known as the STAAR approach, standing for Sequential Thiolactone Amine Acrylate Reaction, allowed for the combinatorial synthesis and in vivo screening of 91 novel lipids, followed by a structure-activity study. This led to the development of CP-LC-0729, an ionizable lipid that significantly surpasses the benchmark in protein expression while showing no in vivo toxicity. Additionally, the STAAR lipid platform was further validated by incorporating a one-step strategy to yield a permanently cationic lipid which was tested following a fifth-lipid formulation strategy. The in vivo results showed a highly selective lung delivery with a 32-fold increase in protein expression, outperforming current endogenous targeting strategies. All these findings underscore the potential of lipid CP-LC-0729 and the STAAR lipid platform in advancing the efficiency and specificity of mRNA delivery systems, while also advancing the development of new ionizable lipids.

Keywords: lipid nanoparticle ; ionizable lipid ; drug delivery ; lipids ; extrahepatic ; lung targeting ; mRNA therapeutics

Purchased from AmBeed: ;

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.

Alternative Products

Product Details of [ 27578-60-5 ]

CAS No. :27578-60-5
Formula : C7H16N2
M.W : 128.22
SMILES Code : NCCN1CCCCC1
MDL No. :MFCD00006516
InChI Key :CJNRGSHEMCMUOE-UHFFFAOYSA-N
Pubchem ID :33944

Safety of [ 27578-60-5 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H226-H314
Precautionary Statements:P280-P305+P351+P338-P310
Class:8(3)
UN#:2734
Packing Group:

Computational Chemistry of [ 27578-60-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 43.17
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.

1.97
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

0.44
Log Po/w (WLOGP)?

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

0.05
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.

0.57
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

0.83
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.77

Water Solubility

Log S (ESOL):?

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

-0.78
Solubility 21.3 mg/ml ; 0.166 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.

-0.62
Solubility 30.6 mg/ml ; 0.239 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

-1.01
Solubility 12.4 mg/ml ; 0.0966 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.

-6.77 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)

1.01

Application In Synthesis of [ 27578-60-5 ]

* 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 [ 27578-60-5 ]

[ 27578-60-5 ] Synthesis Path-Downstream   1~12

  • 1
  • [ 110-89-4 ]
  • [ 926-39-6 ]
  • [ 27578-60-5 ]
  • 2
  • [ 27578-60-5 ]
  • [ 42926-52-3 ]
  • 2-ethoxy-benzoic acid-(2-piperidino-ethylamide) [ No CAS ]
  • 3
  • [ 27578-60-5 ]
  • [ 33045-53-3 ]
  • [ 102535-21-7 ]
  • 4
  • [ 27578-60-5 ]
  • [ 6492-86-0 ]
  • 6-Amino-2-(2-piperidin-1-yl-ethyl)-benzo[de]isoquinoline-1,3-dione [ No CAS ]
  • 5
  • [ 27578-60-5 ]
  • [ 27018-76-4 ]
  • 1-benzyl-1<i>H</i>-indole-3-carboxylic acid (2-piperidin-1-yl-ethyl)-amide [ No CAS ]
  • 6
  • [ 27578-60-5 ]
  • [ 5147-80-8 ]
  • [(2-piperidinoethylamino)(3-piperidinopropylamino)methylene]malononitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% Example 1 [(2-Piperidinoethylamino)(3-piperidinopropylamino) methylene]malononitrile (Compound 1) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (300 mg, 1.76 mmol) was dissolved in THF (4 mL), and a solution obtained by dissolving 3-piperidinopropylamine (251 mg, 1.76 mmol) in THF (1 mL) was added thereto. After stirring the mixture at room temperature for 1.5 hours, a solution obtained by dissolving 1-(2-aminoethyl) piperidine (226 mg, 1.76 mmol) in THF (1 mL) was added thereto, followed by stirring at room temperature for 1.5 hours, and further stirring at 30C for 5 hours. After cooling, the resulting mixture was added with water, and the pH of the mixture was adjusted to 4 with 2 mol/L hydrochloric acid. Then, the pH of the mixture was adjusted to 9 with a saturated aqueous sodium hydrogen carbonate solution, and the precipitated solid was obtained by filtration. The obtained solid was washed with water, triturated with diisopropyl ether and recrystallized from n-hexane/ethyl acetate, to obtain the titled compound (273 mg, 45%) as a white solid.
  • 7
  • [ 27578-60-5 ]
  • [ 5147-80-8 ]
  • [(2-piperidinoethylamino)(4-piperidinopiperidino)methylene]malononitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% Example 143 [(2-Piperidinoethylamino)(4-piperidinopiperidino) methylene]malononitrile (Compound 143) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (242 mg, 1.42 mmol) was dissolved in ethanol (2 mL) and the solution was added with a solution of 4-piperidinopiperidine (251 mg, 1.49 mmol) in ethanol (3 mL), followed by stirring at room temperature for 0.5 hour. The mixture was added with 1-(2-aminoethyl)piperidine (0.319 mL, 2.24 mmol) and stirred at 70C for 6 hours. Further, the mixture was added with 1-(2-aminoethyl) piperidine (0.213 mL, 1.49 mmol) and stirred at 70C for 2 hours. After cooling, the reaction mixture was added with saturated brine and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-hexane/ethyl acetate (1:1)) to obtain the titled compound (465 mg, 88%) as a yellow oily substance. 1H NMR (CDCl3, δppm): 1.38-1.69 (m, 13H), 1.94 (d, J=11.2Hz, 2H), 2.34-2.57 (m, 12H), 3.08 (t, J = 12.9 Hz, 2H), 3.31-3.38 (m, 2H), 3.88 (d, J = 12.9 Hz, 2H), 5.97 (br s, 1H). APCIMS m/z: [M+H]+371. Melting point: 198-200C.
  • 8
  • [ 27578-60-5 ]
  • [ 58656-98-7 ]
  • [ 733785-78-9 ]
YieldReaction ConditionsOperation in experiment
64% at 120℃; Step 1: tert-Butyl 4- (2- (piperidin-1-yl) ethylamino) benzoate (187) [0348] tert-Butyl 4-FLUOROBENZOATE 185 (0.502g, 2.55 MMOL) and 24PIPERIDIN-1-YL) ETHANAMINE 186 (1.46 mL, 10.21 MMOL) were stirred neat at 120C overnight then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate (LX), brine (LX), dried over magnesium sulfate and evaporated to give 187 (0.501g, 64%). H NMR: (DMSO) 6 (ppm): 400 MHz, (DMSO) d (ppm): 7.59 (d, J= 8.8 Hz, 2H), 6.55 (d, J= 8.8 Hz, 2H), 6.24 (t, J= 5.1 Hz, 1H), 4.11 (m, 2H), 3.21 to 3.13 (m, 6H), 2.44 (t, J= 7.1 Hz, 2H), 2.37 (m, 2H), 1.49 (s, 9H), 1.47 to 1.38 (m, 2H). MS: 304.22 (CALC), 249.1 (M-T8U).
  • 9
  • [ 27578-60-5 ]
  • [ 207399-07-3 ]
  • [ 1255954-14-3 ]
  • 10
  • [ 27578-60-5 ]
  • [ 171243-30-4 ]
  • [ 1415400-66-6 ]
YieldReaction ConditionsOperation in experiment
65% In dichloromethane; at 20℃; for 0.5h; General procedure: To a solution of benzoyl chloride (1 mmol) in dry dichloromethane (10 ml) was added amine (1 mmol), and the mixture was stirred for 0.5 h at room temperature. After solvent evaporation, the crude product was purified by column chromatography on silica (CHCl3:CH3CH2OH = 9:1) resulting in yellow thick oil and crystallized from the dichloromethane-petroleum ether mixture.
  • 11
  • [ 27578-60-5 ]
  • copper(II) nitrate trihydrate [ No CAS ]
  • [ 32596-43-3 ]
  • C22H33ClCu2N5O5(1+)*NO3(1-)*H2O [ No CAS ]
  • 12
  • [ 27578-60-5 ]
  • [ 23351-91-9 ]
  • 5-bromo-N1,N3-bis[2-(piperidin-1-yl)ethyl]benzene-1,3-dicarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h; To a solution of <strong>[23351-91-9]5-bromoisophthalic acid</strong> 1(200 mg, 0.82 mmol) and 1-piperidineethanamine (240 mL, 1.17mmol) in DMF (2.5 mL) was added EDC*HCl (330 mg, 1.73 mmol) and HOBt-H2O (25.2 mg, 0.165 mmol). The reaction mixture was stirred for 16 h at room temperature. 10 mL of saturated NaHCO3 solution was added. The aqueous layer was extracted with DCM(3 10 mL). The combined organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography(DCM/MeOH(NH3), 10:0 to 9.7:0.3 (v/v)). The title compound 14(340 mg, 0.73 mmol, 89percent) was obtained as a white solid. Mp:127.3 C. 1H NMR (300 MHz), d (ppm, CDCl3): 8.23 (t, J = 1.5 Hz,1H); 8.04 (d, J = 1.5 Hz, 2H); 7.46 (t, J = 4.7 Hz, 2H); 3.48 (td, J =5.9 Hz, J = 5.5 Hz, 4H); 2.50 (t, J = 6.1 Hz, 4H); 2.38 (m, 8H); 1.54(m, 8H); 1.40 (m, 4H). 13C NMR (75 MHz), d (ppm, CDCl3): 165.3;136.3; 133.2; 123.7; 123.0; 57.4; 54.3; 36.6; 25.7; 24.2. LC?MS(ESI) m/z Calculated: 465.2?467.2, Found: 465.0?466.9, 233.1?234.0 [(M+2H)/2]+.
 

Historical Records

Technical Information

Categories

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[ 27578-60-5 ]

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