Hypoglycemic Agents. I.1 Chemical Properties of β-Phenethylbiguanide.2 A New Hypoglycemic Agent3

Shapiro, Seymour L.; Parrino, Vincent A.; Freedman, Louis

doi:10.1021/ja01518a052

Cited by 57 publications

(16 citation statements)

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“…Therefore, in order to isolate the metabolism product the bile was the best starting material. In this way we were able to isolate, in a good yield The structure of this compound (III) was verified by synthesis, which was carried out according to a method described by Shapiro, Parrino & Freedman (1959) On the basis of radioactivity measurements made on the separated bile fractions, it is possible to state that in the bile there is 70% of metabolite and 25% of unchanged starting material. Moreover, in chromatograms a radioactive tail between the spots of the two compounds was detected.…”

Section: Resultsmentioning

confidence: 97%

Some Aspects of the Metabolism of Triazine Derivatives Active in Experimentally Induced Virus Infections

Cresseri¹,

Giraldi²,

Logemann³

et al. 1966

British Journal of Pharmacology and Chemotherapy

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In a recent paper we reported on the metabolism of 4-acetamido-2-morpholino-1,3,5-triazine (Angelucci, Artini, Cresseri, Giraldi, Logemann, Nannini & Valzelli, 1965). In the course of our research we synthesized a great number of symmetrical triazines which were screened in antiviral tests. In doing so, we found another compound, 2-[(o-phenoxy-phenyl)-amino]-4-amino-1,3,5-triazine (I), which had an activity even higher than 4-acetamido-2-morpholino-1,3,5-triazine. Compound I is more active in reducing the intensity of pulmonary lesions induced in mice by influenza virus type B. Moreover, this compound, like 4-acetamido-2-morpholino-1,3,5-triazine does not affect the replication of viruses in fertile eggs (Angelucci, 1961;Angelucci, Artini, Giraldi, Logemann & Nannini, 1961; Angelucci, Artini, Giraldi, Logemann, Nannini & Valzelli, 1963a,b).Consequently, we believe that compound I might have been transformed, in vivo, into an active metabolite, and it was interesting to investigate its fate in animals. METHODSRadioactive (2-[(o-phenoxy-phenyl)-amino]-4-amino-1,3,5-triazine was prepared by labelling the triazine ring with 'IC at position 6, according to the method already described (Angelucci et al., 1965). The substance had a specific activity of 100 yc/mM.In the experiment male and female Wistar albino rats, weighing 200 g on average and fasted for 15 hr, were used. During the experiment the animals were kept in single metabolism cages and were fed the usual laboratory diet after 12 hr from the beginning of treatment. Doses of 28 and 85 mg/kg of the labelled compound, dissolved in 1,2-propandiol, were administered by subcutaneous and intraperitoneal injection to two groups of animals, and a dose of 28 mg/kg,

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Section: Resultsmentioning

confidence: 97%

Some Aspects of the Metabolism of Triazine Derivatives Active in Experimentally Induced Virus Infections

Cresseri¹,

Giraldi²,

Logemann³

et al. 1966

British Journal of Pharmacology and Chemotherapy

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“…Metformin is synthesized by heating dimethylamine hydrochloride and cyanoguanidine (Werner & Bell, ). Whereas, phenformin is obtained by heating phenethylamine and cyanoguanidine (37% yield; Shapiro, Parrino, & Freedman, ). Imeglimin is synthesized by adding acetaldehyde to a solution of metformin hydrochloride, sodium hydroxide, and water (93% yield; List & Cheng, ).…”

Section: Synthesismentioning

confidence: 99%

A review of phenformin, metformin, and imeglimin

Yendapally

Sikazwe

Kim

et al. 2020

Drug Development Research

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Diabetes mellitus is a serious metabolic disorder affecting millions of people worldwide. Phenformin and metformin are biguanide antidiabetic agents that are conveniently synthesized in a single-step chemical reaction. Phenformin was once used to lower blood glucose levels, but later withdrawn from the market in several countries because it was frequently associated with lactic acidosis. Metformin is still a widely prescribed medication for the treatment of type 2 diabetes despite the introduction of several newer antidiabetic agents. Metformin is administered orally and has desirable pharmacokinetics. Incidence of metformin-induced lactic acidosis is serious but very rare. Imeglimin, a novel molecule being investigated by Poxel and Sumitomo Dainippon Pharma in Japan, is currently in clinical trials for the treatment of type 2 diabetes. Unlike metformin, imeglimin is a cyclic molecule containing a triazine ring.However, like metformin, imeglimin is also a basic small molecule. Imeglimin is synthesized from metformin as a precursor via a single step chemical reaction. Recent mechanism of action studies suggests that imeglimin improves mitochondria function, when given in combination with metformin it helps achieve better glycemic control in patients with type 2 diabetes. We herein describe and compare the current status, synthesis, physicochemical properties, pharmacokinetic parameters, mechanism of action, and preclinical/clinical studies of metformin and imeglimin.

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“…CGN is an impurity from the synthesis of MET, which involves the reaction of dimethylamine hydrochloride with CGN at elevated temperature (Fig. A) . Thus, the quantitation of CGN in raw material and pharmaceutical products is necessary for the quality control and stability of MET.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous analysis of metformin and cyanoguanidine by capillary zone electrophoresis and its application in a stability study

Doomkaew

Prutthiwanasan

Suntornsuk

2014

J of Separation Science

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A capillary zone electrophoresis method was established for stability study of metformin (MET). MET and cyanoguanidine (CGN; a major degradation product) were well separated (with a resolution of 38.9) in 40 mM citrate buffer (pH 6.7) using a fused-silica capillary with an effective length of 60 cm and an inner diameter of 50 μm, injection at 50 mbar for 5 s at 30°C with an applied voltage of 15 kV and diode array detection at 214 nm. Method validation showed good linearity (r(2) > 0.99), precision (%RSDs < 1.98%), and accuracy (%recovery between 98.3 and 100.9%). Limits of detection and quantification were <30 and 100 μg/mL, respectively. The method was robust upon alteration of pH and voltage (%RSDs < 1.99%). Stability profiles of metformin from 11 stress conditions and the degradation kinetics could be established, using the simple capillary zone electrophoresis system. A mechanism for the degradation of MET was also proposed. MET was stable in neutral hydrolysis, but degraded under alkaline hydrolysis and oxidation. Under both conditions, CGN was quantified as the degradation product. An assay of MET in raw material and tablets showed that content of the drugs in all samples met the requirements of pharmacopeias and CGN was not detected.

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Hypoglycemic Agents. I.¹ Chemical Properties of β-Phenethylbiguanide.² A New Hypoglycemic Agent³

Cited by 57 publications

References 0 publications

Some Aspects of the Metabolism of Triazine Derivatives Active in Experimentally Induced Virus Infections

Some Aspects of the Metabolism of Triazine Derivatives Active in Experimentally Induced Virus Infections

A review of phenformin, metformin, and imeglimin

Simultaneous analysis of metformin and cyanoguanidine by capillary zone electrophoresis and its application in a stability study

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