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Chemical Structure| 32213-95-9 Chemical Structure| 32213-95-9
Chemical Structure| 32213-95-9

H-Asp(ome)-OMe HCl

CAS No.: 32213-95-9

H-Asp(ome)-OMe HCl is an aspartic acid derivative, commonly used in peptide synthesis and drug development.

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Cat. No.: A272538 Purity: 98%

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Kim, Jaejeong ; Kang, Changyu ; Yoo, Jin-Wook ; Yoon, In-Soo ; Jung, Yunjin ;

Abstract: The selective agonist of β2-adrenergic receptor mirabegron (MBG), clinically used to treat overactive bladders, exerts beneficial effects in animal models of colitis. Here, we aimed to enhance the therapeutic activity and safety of MBG as an anticolitic drug by implementing colon-targeted drug delivery using a prodrug approach. MBG was azo-linked with salicylic acid (SA) to yield SA-conjugated MBG (MAS), which was conjugated with aspartic acid (Asp) and glutamic acid (Glu) to yield more hydrophilic derivatives: Asp-conjugated MAS (MAS-Asp) and Glu-conjugated MAS (MAS-Glu). MBG derivatives reduced the distribution coefficient and cell permeability of MBG, which were greater with the amino acid-conjugated MAS than with MAS. MBG derivatives were cleaved to release MBG in the cecal contents. Upon oral gavage, compared with MBG, MBG derivatives delivered greater amounts of MBG to the cecum while limiting the systemic absorption of MBG, and the amino acid-conjugated MAS exhibited a greater performance than MAS. In a rat colitis model, MBG derivatives were more effective than MBG in ameliorating colonic damage and inflammation, and the amino acid-conjugated MAS was more potent than MAS. MAS-Glu was therapeutically superior to sulfasalazine, a current drug to treat inflammatory bowel disease, against rat colitis. Moreover, MBG activated the anti-inflammatory nuclear factor erythroid 2-related factor 2 (Nrf2)-hemeoxygenase (HO)-1 pathway in inflamed colonic tissue, and the MAS-Glu-mediated amelioration of colitis was significantly compromised by an HO-1 inhibitor. Taken together, colon-targeted delivery of MBG may enhance the anticolitic activity, reduce the risk of systemic side effects of MBG, and elicit the therapeutic effects, at least partly by activating the Nrf2-HO-1 pathway.

Keywords: colon-targeted drug delivery ; prodrug ; mirabegron ; inflammatory bowel disease ; beta-3 adrenergic receptor ; nuclear factor erythroid 2-related factor 2

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Kim, Jaejeong ; Kang, Changyu ; Jung, Yunjin ;

Abstract: Purpose: In our previous study, (RLZ) azo-linked to (RAS) was prepared as a colon-targeted RLZ prodrug against rat colitis. However, was not a satisfactory colon-targeted prodrug because of its non-negligible systemic absorption, leading to low colonic delivery efficiency and the ability to limit the systemic absorption of RLZ. This study aimed to improve the colon specificity and anticolitic activity of . Methods: (SA) was conjugated with the acidic amino acids (Asp) and (Glu) and subsequently azo-coupled with to yield Asp-conjugated (RAS-Asp) and Glu-conjugated (RAS-Glu). Results: Amino acid-conjugated lowered the distribution coefficient and cell permeability of while exhibiting a release profile of RLZ similar to that of in the cecal contents. Upon oral gavage, amino acid-conjugated delivered a larger amount of RLZ to the cecum than . The ability of amino acid-conjugated to limit the systemic absorption of RLZ was greater than that of . No significant differences were observed in the colon-specific performance between RAS-Asp and RAS-Glu. In a DNBS-induced rat colitis model, amino acid-conjugated was more effective than in ameliorating colonic damage and inflammation and modulating the anti-inflammatory GSK3β-IL-10 pathway in the inflamed colon, without a significant difference between RAS-Asp and RAS-Glu. Conclusion: Conjugation of acidic amino acids with improved the colon specificity, anticolitic activity, and safety of . N-Salicyloyl acidic amino acids may act as high-performance colon-specific promiety for a candidate drug modifiable to a colon-targeted prodrug with an azo bond as a colon-specific link.

Keywords: ; Colon-targeted prodrug ; Colitis ; Acidic amino acids ; High performance colon-specific promoiety

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Kang, Changyu ; Kim, Jaejeong ; Jeong, Yeonhee ; Yoo, Jin-Wook ; Jung, Yunjin ;

Abstract: Background/Objectives: In addition to oncological applications, poly(ADP-ribose) polymerase (PARP) inhibitors have potential as anti-inflammatory agents. Colon-targeted delivery of PARP inhibitors has been evaluated as a pharmaceutical strategy to enhance their safety and therapeutic efficacy against gut inflammation. Methods: Colon-targeted PARP inhibitors 5-aminoisoquinoline (5-AIQ) and 3-aminobenzamide (3-AB) were designed and synthesized by azo coupling with salicylic acid (SA), yielding 5-AIQ azo-linked with SA (AQSA) and 3-AB azo-linked with SA (ABSA). Additional conjugation of AQSA with acidic amino acids yielded glutamic acid-conjugated AQSA (AQSA-Glu) and aspartic acid-conjugated AQSA, which further increased the hydrophilicity of AQSA. Results: The distribution coefficients of PARP inhibitors were lowered by chemical modifications, which correlated well with drug permeability via the Caco-2 cell monolayer. All derivatives were effectively converted to their corresponding PARP inhibitors in the cecal contents. Compared with observations in the oral administration of PARP inhibitors, AQSA-Glu and ABSA resulted in the accumulation of much greater amounts of each PARP inhibitor in the cecum. ABSA accumulated mesalazine (5-ASA) in the cecum to a similar extent as sulfasalazine (SSZ), a colon-targeted 5-ASA prodrug. In the DNBS-induced rat colitis model, AQSA-Glu enhanced the anticolitic potency of 5-AIQ. Furthermore, ABSA was more effective against rat colitis than SSZ or AQSA-Glu, and the anticolitic effects of AQSA-Glu were augmented by combined treatment with a colon-targeted 5-ASA prodrug. In addition, the colon-targeted delivery of PARP inhibitors substantially reduced their systemic absorption. Conclusions: Colon-targeted PARP inhibitors may improve the therapeutic and toxicological properties of inhibitors and synergize the anticolitic effects of 5-ASA.

Keywords: poly(ADP-ribose) polymerase inhibitor ; colon-targeted drug delivery ; colitis ; mesalazine ; prodrug

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Alternative Products

Product Details of H-Asp(ome)-OMe HCl

CAS No. :32213-95-9
Formula : C6H12ClNO4
M.W : 197.62
SMILES Code : N[C@@H](CC(OC)=O)C(OC)=O.[H]Cl
MDL No. :MFCD00038878
InChI Key :PNLXWGDXZOYUKB-WCCKRBBISA-N
Pubchem ID :2734892

Safety of H-Asp(ome)-OMe HCl

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of H-Asp(ome)-OMe HCl

* 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 [ 32213-95-9 ]

[ 32213-95-9 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 24424-99-5 ]
  • [ 32213-95-9 ]
  • [ 130622-08-1 ]
YieldReaction ConditionsOperation in experiment
90% With sodium hydrogencarbonate; In dichloromethane; water; for 4h; Step 1: L-aspartic acid dimethyl ester hydrochloride (5.0 g, 25.3 mmol) was dissolved in dichloromethane (50 mL) and water (25 mL), and sodium bicarbonate (4.25 g, 50.6 mmol) was added to the system. After the mixture was stirred for 4 hours, the mixture was evaporated. The crude product was recrystallized from n-heptane to afford compound 6.1 (5.97 g, yield: 90%) as white solid.
78% With triethylamine; In methanol; at -78 - 20℃; for 18h; Preparation 70 Dimethyl N-(fe/f-butoxycarbonyl)-L-aspartate To a solution of dimethyl L-aspartate hydrochloride (Preparation 71 , 160 g, 0.75 mol) in MeOH (600 mL) at -78C was added triethylamine (200 mL, 1 .50 mol) followed by Boc2O (180 g, 0.83 mol) and the reaction stirred at rom temperature for 18 hours. The reaction was concentrated in vacuo and triturated with THF. The triethylamine hydrochloride was filtered off and the filtrate evaporated to dryness. The residue was dissolved in DCM and purified using silica gel column chromatography eluting with DCM:TBME 100:1 to afford the title compound as a white solid (153.7 g, 78%). 1H NMR (400MHz, CDCI3): delta ppm 1 .40 (s, 9H), 2.70-3.10 (m, 2H), 3.69 (s, 3H), 3.76 (s, 3H), 4.59 (m, 1 H), 5.46 (m, 1 H).
With triethylamine; In dichloromethane; Preparation 33 (-)-Dimethyl (2S)-2-[(tert-butoxycarbonyl)amino]butanedioate A solution of di-tert-butyl dicarbonate (10.3 g, 47 mmol) in dichloromethane (20 ml) was added dropwise to an ice-cooled solution of L-aspartic acid dimethyl ester hydrochloride (9.3 g, 47 mmol) and triethylamine (14.4 ml, 103 mmol) in dichloromethane (60 ml), and the mixture was stirred at room temperature for 18 hours. The solution was diluted with dichloromethane (60 ml), washed sequentially with water (5 ml), 5% aqueous sodium bicarbonate solution (50 ml) and brine (50 ml), then dried (Na2SO4) and evaporated under reduced pressure. The residual oil was triturated with hexane to afford the title compound as a white solid, 11 g. 1H-NMR (CDCl3 300 MHz) delta: 1.45 (s, 9H), 2.81 (dd, 1H), 3.00 (dd, 1H), 3.70 (s, 3H), 3.77 (s, 3H), 4.59 (m, 1H), 5.50 (m, 1H). LRMS: m/z (ES+) 262 [MH+]. [alpha]D=-10.91 (c=0.132, ethanol).
 

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