Preparation of 1-acyloxyethyl esters of 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoe thy l)-1H-tetrazol-5-yl]thio]-methyl]ceph-3-em-4-carboxylic acid (cefotiam) and their oral absorption in mice.

doi:10.7164/ANTIBIOTICS.39.1329

Paper

Preparation of 1-acyloxyethyl esters of 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoe thy l)-1H-tetrazol-5-yl]thio]-methyl]ceph-3-em-4-carboxylic acid (cefotiam) and their oral absorption in mice.

Published Sep 1, 1986 · Y. Yoshimura, N. Hamaguchi, T. Yashiki

The Journal of antibiotics

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15

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Abstract

In a separate study on the orally active acyloxymethyl esters (1) of 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoethyl) - 1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylic acid (cefotiam, CTM), we have shown, by quantitative structure-oral bioavailability (BA) relation analysis, that the R2 group in the acyl group R2CO must have both an adequate lipophilicity (Hansch's lipophilic parameter, pi) and steric hindrance (Taft's Es value). However, to satisfy these requirements, a complex alkyl group R2 must be employed, the ester of which is difficult to synthesize and has unique metabolic fate. In this study, we selected and prepared the 1-acyloxyethyl esters (2) of CTM instead of 1 to avoid R2 groups that are too complicated. We found that the esters (2) gave improved oral BAs over 1: the 1-(3-methyl-valeryloxy)ethyl ester (2h) showed the highest peak plasma CTM level (Cmax) comparable to that obtained after subcutaneous injection of CTM. The 1-(cyclohexylacetoxy)ethyl ester (2t), the 1-(2-ethylbutyryloxy)ethyl ester (2j), and 2h showed BAs near 100%. For these esters (2), good correlations were also observed among the pi, the Es values of R2, and the log Cmax and log BA in the analysis of the quantitative structure-oral bioavailability relation: an ester having an alkyl group as R2 with a pi value of 3.07 or 3.08 and a Es value of -1.04 or -1.29 gave the highest Cmax or BA, respectively. As expected, the optimal pi values are almost the same as those obtained with 1 but the optimal Es values are larger (Es = -2.07). Thus, it has been confirmed by preparing 1-acyloxyethyl esters (2) of CTM that the oral bioavailability of CTM can further be improved without preparing acyloxymethyl esters (1) with a complicated acyl group.

Non-RCT

Animal Study

Study Snapshot

1-acyloxyethyl esters (2) of cefotiam improve oral bioavailability without requiring complex acyl groups, enabling their use in oral dosage forms.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Preparation of 1-acyloxyethyl esters of 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoe thy l)-1H-tetrazol-5-yl]thio]-methyl]ceph-3-em-4-carboxylic acid (cefotiam) and their oral absorption in mice.

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References

Synthesis and oral absorption of acyloxymethyl esters of 7β-( 2-( 2-aminothiazol-4-yl) acetamido) -3-(((1-( 2-dimethylaminoethyl) -1H-tetrazol-5-yl) thio) -methyl) ceph-3-em-4-carboxylic acid (cefotiam)

Orally active prodrugs of cefotiam can be designed with steric hindrance and a promoter with E s value near 2 and value between 2 and 4 for improved bioavailability in mice.

Synthesis and relation between physicochemical properties and oral absorption of 7-O-acylmandelamido-3-methyl-3-cephem-4-carboxylic acids☆

Orally active cephalosporins with a 7-acyl group other than phenylglycine can be effectively absorbed through the gastrointestinal tract when log P and pKa values are in a selected range.

KY-109, a new bifunctional pro-drug of a cephalosporin. Chemistry, physico-chemical and biological properties.

KY-109, a new bifunctional pro-drug, effectively improves oral absorption of the parent drug (KY-087), a cephalosporin similar to cefamandole, in rats.

Synthesis and relationship between physicochemical properties and oral absorption of pivaloyloxymethyl esters of parenteral cephalosporins

Water solubility is crucial in designing orally active ester prodrugs of parenteral cephalosporins, with the best bioavailability achieved by Cefotiam's ester, '1'.

Pharmacology of Cefuroxime as the 1-acetoxyethyl ester in volunteers

Cefuroxime axetil is a well-tolerated and well-tolerated oral antibiotic with similar bioavailability and pharmacokinetics to ampicillin, with no significant differences in bowel flora and habit changes compared to ampicillin.

Citations

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Novel C5-linked tetrazole ribonucleoside phosphoramidites can be used to determine which nucleobases in ribozymes function as acids or bases, aiding in ribozyme general acid and base catalysis studies.

Prodrugs of butyric acid. Novel derivatives possessing increased aqueous solubility and potential for treating cancer and blood diseases.

Butyric acid prodrugs with increased aqueous solubility show potential for treating cancer and blood diseases, with promising results for prostate carcinoma, myeloid leukemia, and erythroleukemia.

Prodrugs of CL316243: a selective beta3-adrenergic receptor agonist for treating obesity and diabetes.

Prodrugs of CL316243, a selective beta3-adrenergic receptor agonist, significantly improve oral bioavailability in both rodent and primate models for treating obesity and Type II diabetes.

Synthesis of HR 916 B: The First Technically Feasible Route to the 1‐(Pivaloyloxy)ethyl Esters of Cephalosporins

This study developed a technically feasible route to the orally active 1-(RS)-(pivaloyloxy)ethyl ester of cephalosporin cefdaloxime, with a 39% overall yield compared to AMCA (8) and 15% compared to ACA (7).

Studies on orally active cephalosporins. II. Synthesis and structure-activity relations of new [(E) or (Z) 3-substituted carbamoyloxy]-1-propenyl cephalosporins.

The compound with N,N-dimethylcarbamoyloxy at C-3 position shows good oral absorption and well-balanced antibacterial activity in oral cephalosporins.