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Chemical Structure| 41838-46-4 Chemical Structure| 41838-46-4

Structure of 41838-46-4

Chemical Structure| 41838-46-4

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Product Citations

Product Citations

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

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Product Details of [ 41838-46-4 ]

CAS No. :41838-46-4
Formula : C6H14N2
M.W : 114.19
SMILES Code : CN1CCC(N)CC1
MDL No. :MFCD01570549
InChI Key :ALOCUZOKRULSAA-UHFFFAOYSA-N
Pubchem ID :2737531

Safety of [ 41838-46-4 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H225-H314
Precautionary Statements:P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405
Class:8(3)
UN#:2920
Packing Group:

Computational Chemistry of [ 41838-46-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 8
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 38.36
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.

1.61
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

-0.12
Log Po/w (WLOGP)?

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

-0.34
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.

0.21
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

0.27
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.33

Water Solubility

Log S (ESOL):?

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

-0.47
Solubility 38.5 mg/ml ; 0.337 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.

-0.04
Solubility 104.0 mg/ml ; 0.91 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

-0.34
Solubility 51.6 mg/ml ; 0.452 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.

-7.08 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)

1.0

Application In Synthesis of [ 41838-46-4 ]

* 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 [ 41838-46-4 ]

[ 41838-46-4 ] Synthesis Path-Downstream   1~15

  • 1
  • [ 41838-46-4 ]
  • [ 33045-53-3 ]
  • [ 113681-64-4 ]
  • 2
  • [ 41838-46-4 ]
  • [ 106157-91-9 ]
  • [ 50607-30-2 ]
  • 2-(2-Amino-pyrimidin-4-yl)-1-(1-methyl-piperidin-4-yl)-1.5.6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one [ No CAS ]
  • 3
  • [ 41838-46-4 ]
  • [ 1137867-66-3 ]
  • [ 1137868-52-0 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Product distribution / selectivity; Compound 116: 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9- tetrahydro-5H-pyrimido[4,5-b][l,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(l- methylpiperidin-4-yl)benzamide; The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo- 6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][l,4]diazepin-2-ylamino)-2-fluoro-5- <n="360"/>methoxybenzoic acid and l-methylpiperidin-4-amine as described in the general procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1U NMR (400 MHz, DMSO-J6) delta ppm 1.60-1.73 (m, 11 H), 1.88 - 2.21 (m, 8 H) 2.78 (br. s., 2 H) 3.73 (br. s., 1 H) 3.91 (s, 3 H) 4.08 (t, J=13.8 Hz, 2 H) 4.81 (d, J=8.1 Hz, 1 H) 7.18 (d, J=6.6 Hz, 1 H) 7.91 (br. s., 1 H) 8.04 (s, 1 H) 8.24 (d, J=13.4 Hz, 1 H) 8.30 (s, 1 H). [M+H] calc'd for C27H34F3N7O3, 562; found 562.; The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5- methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][l,4]diazepin-2-ylamino)-2-fluoro-5- methoxybenzoic acid (obtained above, 12 mg) as described in the general procedure for amide bond synthesis using HATU and l-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base (8 mg, 55percent). 1H NMR (400 MHz, DMSO-J6) delta ppm 1.60-1.73 (m, 11 H), 1.88 - 2.21 (m, 8 H) 2.78 (br. s., 2 H) 3.73 (br. s., 1 H) 3.91 (s, 3 H) 4.08 (t, J= 14 Hz, 2 H) 4.81 (d, J= 8 Hz, 1 H) 7.18 (d, J= 7 Hz, 1 H) 7.91 (br. s., 1 H) 8.04 (s, 1 H) 8.24 (d, J= 13 Hz, 1 H) 8.30 (s, 1 H). [M+H] calc'd for C27H34F3N7O3, 562; found 562.
(I-176) To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid (I-169), 0.06 g (0.16 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.06 mL (0.32 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.04 g (0.32 mmole) of 4-amino-1-methylpiperidine was added. The mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with 1M sodium hydroxide solution then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluding with methanol-dichloromethane (gradient, 0:100-20:80) to give 0.038 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-176).
  • 4
  • [ 41838-46-4 ]
  • [ 85822-16-8 ]
  • [ 1336912-64-1 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; at 20 - 25℃; for 0.5h; Intermediate 14-Formyl-N-( 1 -methylpiperidin-4-yl)benzenesulfonamide1 step a.4-Formylbenzene-l-sulfonyl chloride (0.5 g, 2.44 mmol) was stirred with l-methyl-4- aminopiperidine (CAS RN 41838-46-4) (0.28 g, 2.47 mmol) and triethylamine (0.5 mL, 3.70 mmol) in DCM (10 mL) at rt for 30 min. When the sulfonyl chloride had been used up by tic the reaction mixture was concentrated to give an orange oil (1.1 g) and used without further purification in the next step.
  • 5
  • [ 41838-46-4 ]
  • [ 85822-16-8 ]
  • [ 1336912-20-9 ]
  • 6
  • [ 41838-46-4 ]
  • [ 3314-30-5 ]
  • [ 1370428-12-8 ]
  • 7
  • [ 41838-46-4 ]
  • [ 3314-30-5 ]
  • [ 1370436-48-8 ]
YieldReaction ConditionsOperation in experiment
With 4A molecular sieves; In ethanol; for 4h;Reflux; 59 B1 /-/-Benzimidazole-2-carboxaldehyde (781 mg, can be prepared according to Fegy, K. Angewandte Chemie Int Ed, 1998, vol. 37, 1270-1273), 4-amino-1 -methylpiperidine (781 mg) and 4A molecular sieves (15g) in ethanol (1 OOmL) are heated under reflux for 4h. The mixture is then filtered and the filtrate concentrated under reduced pressure to yield (1 - -benzimidazol-2-ylmethylene)(1 -methylpiperidin-4-yl)amine as a beige solid.
In ethanol; for 4h;Molecular sieve; Reflux; 1 H-Benzimidazole-2-carboxaldehyde (781 mg, can be prepared according to Fegy, K. Angewandte Chemie Int Ed, 1998, vol. 37, 1270-1273), 4-amino-1-methylpiperidine (781 mg) and 4A molecular sieves (15g) in ethanol (100mL) are heated under reflux for 4h. The mixture is then filtered and the filtrate concentrated under reduced pressure to yield (1H-benzimidazol-2-ylmethylene)(1-methylpiperidin-4-yl)amine as a beige solid.
  • 8
  • [ 41838-46-4 ]
  • [ 630125-49-4 ]
  • [ 1529769-59-2 ]
YieldReaction ConditionsOperation in experiment
99% With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃;Inert atmosphere; Add l-bromo-3-nitro-5-(trifluoromethyl)benzene (3 g, 11.11 mmol), CS2CO3 (9.5 g, 27.78 mmol), l-methylpiperidin-4-amine (1.9 g, 16.67 mmol) to 1,4-dioxane (25 mL), then under N2, add Pd(OAc)2 (50 mg, 0.22 mmol) and BINAP (207 mg, 0.33 mmol). Stir the reaction at 120C under N2 overnight. TLC (DCM:MeOH=10:l) shows the reaction is complete. Cool to room temperature and filter off the solid. Concentrate the filtrate to get the crude product. Purification by chromatography (silica gel, DCM:MeOH=10:l) affords the title compound (3.44 g, 99%). MS: (M+l): 304
99% With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃;Inert atmosphere; Add <strong>[630125-49-4]1-bromo-3-nitro-5-(trifluoromethyl)benzene</strong> (3 g, 11.11 mmol), Cs2CO3 (9.5 g, 27.78 mmol), 1-methylpiperidin-4-amine (1.9 g, 16.67 mmol) to 1,4-dioxane (25 mL), then under N2, add Pd(OAc)2 (50 mg, 0.22 mmol) and BINAP (207 mg, 0.33 mmol). Stir the reaction at 120 C. under N2 overnight. TLC (DCM:MeOH=10:1) shows the reaction is complete. Cool to room temperature and filter off the solid. Concentrate the filtrate to get the crude product. Purification by chromatography (silica gel, DCM:MeOH-10:1) affords the title compound (3.44 g, 99%). MS: (M+1): 304.
  • 9
  • [ 41838-46-4 ]
  • [ 70049-46-6 ]
  • C16H20ClN3O [ No CAS ]
  • 10
  • [ 41838-46-4 ]
  • [ 32608-29-0 ]
  • C16H20ClN3O [ No CAS ]
  • 11
  • [ 41838-46-4 ]
  • [ 103058-87-3 ]
  • N-((5-bromo-2-methoxypyridin-3-yl)methyl)-1-methylpiperidin-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 22h; 5-Bromo-2-methoxynicotinaldehyde (472 mg, 2.18 mmol) and 1-methylpiperidin-4- amine (249 mg, 2.18 mmol) were stirred in methanol (10 mL). Acetic acid (0.12 mL) and sodium cyanoborohydride (137 mg, 2.18 mmol) were then added and the mixturewas stirred at room temperature for 22 h. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane and a saturated aqueous sodium hydrogen carbonate solution. The phases were separated. The aqueous layer was extracted with dichloromethane. The combined organics were dried over anhydrous magnesium sulphate, filtered and evaporated under reducedpressure to give 647 mg (94% yield) of the title compound.LRMS (M+1): 314, 3161H NMR (400 MHz, Chloroform-d) 6 ppm 1.44 (2H, m), 1.88 (2H, m), 2.26 (3H, s), 2.43(1 H, m), 2.81 (2H, m), 3.73 (2H, s), 3.93 (3H, s), 7.69 (1 H, d, J = 2.4 Hz), 8.08 (1 H, d, J= 2.4 Hz)
  • 12
  • [ 41838-46-4 ]
  • [ 103058-87-3 ]
  • tert-butyl((5-bromo-2-methoxypyridin-3-yl)methyl)(1-methylpiperidin-4-yl)carbamate [ No CAS ]
  • 13
  • [ 41838-46-4 ]
  • [ 404844-11-7 ]
  • N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(((1-methylpiperidin-4-yl)amino)methyl)benzamide [ No CAS ]
  • 14
  • [ 41838-46-4 ]
  • [ 594839-88-0 ]
  • C20H19Cl2N3O2 [ No CAS ]
  • 15
  • [ 41838-46-4 ]
  • [ 110931-77-6 ]
  • 4-(2,4-difluorophenyl)-N-(1-methylpiperidin-4-yl)-4-oxobutyramide [ No CAS ]
 

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Technical Information

Categories

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