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Structure of 41838-46-4
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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.
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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.
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Keywords: lipid nanoparticle ; ionizable lipid ; drug delivery ; lipids ; extrahepatic ; lung targeting ; mRNA therapeutics
Show More >
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 |
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: | Ⅱ |
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 |
29.26 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.61 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.12 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.34 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.21 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.27 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.33 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.47 |
Solubility | 38.5 mg/ml ; 0.337 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.04 |
Solubility | 104.0 mg/ml ; 0.91 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.34 |
Solubility | 51.6 mg/ml ; 0.452 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 |
-7.08 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) |
1.0 |
* 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 |
---|---|---|
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). |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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) |
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