Rilmazafone hydrochloride (450191S)
(Synonyms: 利马扎封盐酸盐,450191S) 目录号 : GC31257
Rilmazafone hydrochloride (450191S) (450191S) 是苯二氮卓 (omega) 配体。
Cas No.:85815-37-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Animal experiment: | Mice[2]Adult male rats of the Jcl Sprague-Dawley strain, 7-8 weeks old, are used for the experiments. The animals are kept in an air-conditioned room (25±1°C, 50-60% humidity) lighted 12 hr a day (8:00-20:00) and maintain on com mercial rat chow and water ad libitum. Rilmazafone is dissolved in 5% (w/v) arabic gum at 20 or 60 mg/mL, and the resulting solution is administered orally to rats at 1.0 mL/100 g body weight for 3-5 days. Typical inducers, phenobarbital (in physiological saline) and beta-naphthoflavone (in sesame oil), are administered intraperitoneally at a dose of 40 mg/kg, once daily for 3 days. The animals are fasted for 24 hr after the last adminis tration of Rilmazafone or inducers, and then the test solution of Rilmazafone (20 mg/mL of 5% arabic gum) is given orally to rats at a dose of 200 mg/kg. Heparinized blood samples are obtained from the abdominal aorta under ether anesthesia and centrifuged immediately to obtain plasma samples using an Eppendorf centrifuge Type 5414S. |
References: [1]. Yasui M, et al. [Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes]. Nihon Shinkei Seishin Yakurigaku Zasshi. 2005 Jun;25(3):143-51. | |
Rilmazafone hydrochloride (450191S) is a new sleep inducer.
When the animals are pretreated with high doses of Rilmazafone hydrochloride (450191-S; 200 or 600 mg/kg for 5 or 3 days, respectively) to induce hepatic drug-metabolizing enzymes, plasma concentrations of the metabolites after oral administration of a dose of 200 mg/kg of Rilmazafone decrease markedly depending on the induced enzyme activity. Pretreatment of rats with phenobarbital also causes decreased plasma levels of metabolites, which are almost the same as those in Rilmazafone-pretreatment. On the other hand, administration of beta-naphthoflavone to rats leads to higher plasma levels of metabolites, and slower elimination compared with those in the control and Rilmazafone or Phenobarbital pretreated rats. Rilmazafone is demonstrated to stimulate the hepatic drug-metabolizing enzymes in rats, mice and dogs, which is accompanied by a marked reduction in the pharmacological activity of pentobarbital in rats. The induction of hepatic enzyme activities by Rilmazafone is detected only when the plasma concentrations of its metabolites are very high[1].
[1]. Matsubara T, et al. Effect of change of hepatic drug-metabolizing activity on plasma concentrations of major metabolites of the new sleep inducer 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative. Jpn J Pharmacol. 1987 Aug;44(4):429-36.
| Cas No. | 85815-37-8 | SDF | |
| 别名 | 利马扎封盐酸盐,450191S | ||
| Canonical SMILES | NCC(NCC1=NC(C(N(C)C)=O)=NN1C2=C(C=C(Cl)C=C2)C(C3=C(C=CC=C3)Cl)=O)=O.Cl | ||
| 分子式 | C21H21Cl3N6O3 | 分子量 | 511.79 |
| 溶解度 | DMSO : 250 mg/mL (488.48 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9539 mL | 9.7696 mL | 19.5393 mL |
| 5 mM | 0.3908 mL | 1.9539 mL | 3.9079 mL |
| 10 mM | 0.1954 mL | 0.977 mL | 1.9539 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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[Pharmacological studies of a new sleep inducer, 1H-1,2,4-triazolyl benzophenone derivatives (450191-S, rilmazafone hydrochloride) (VII). Comparison of sleep-inducing activities between young and elderly rhesus monkeys]
The sleep-inducing activities of 450191-S (rilmazafone hydrochloride) were compared among two groups of elderly and one group of young rhesus monkeys, and the relationship between blood levels of five active metabolites of 450191-S and sleep-inducing activities was also examined. Oral administration of 450191-S, 1 mg/kg, caused the quick appearance of slow wave deep sleep (SWDS) and its stable continuity in elderly monkeys, and no significant differences in various sleep parameters were observed among the two groups of eight elderly monkeys. An increase of SWDS was always accompanied by a high blood level of active metabolite M-2. On the other hand, in the young rhesus monkey group, the amount of SWDS and its mean continuity were significantly less, and differences were evident in sleep parameters obtained from a nocturnal 14 hr observation. In conclusion, the difference of sleep-inducing activities between elderly and young monkeys seem to be caused by a difference in the blood level of active metabolites of 450191-S, particularly M-2.
Safety evaluation and drug development based on biological fate of drugs -efforts made to overcome drug interaction in drug development-
1. Assay methods to detect drug interaction in toxicological samples were established by determining cytochrome P450 content and its activity in liver samples. The O-dealkylation reaction of 7-alkoxycoumarin was indicated to reflect changes in the molecular forms of P450s, and the enzyme induction or inhibition in the toxicological samples was easily detected by using the established methods. 2. During toxicological studies of 450191-S or the sleep inducer rilmazafone, a phenobarbital type-induction of hepatic drug metabolizing enzymes was observed in animals, and the doses required for the induction differed markedly between rats and dogs. Enzyme induction was caused by some specific metabolites of 450191-S, and the plasma concentrations of these metabolites were comparable when the enzyme induction was developed in both animals. 3. A nonsteroidal antiinflammatory compound 480156-S showed a slight or no effect on microsomal drug metabolizing activity in rats. On the other hand, repeated administration of this compound to humans resulted in a marked decrease in the oxidative metabolism of 480156-S, followed by a marked increase in the plasma concentrations of the compound. When volunteers were given 480156-S followed by several drugs, such as tolubutamide, the plasma clearance was delayed remarkably, indicating a severe drug interaction. 4. Cytochrome P450 belonging to the CYP2C family was indicated to participate in the oxidative metabolism of 480156-S in both rat and human liver microsomes. The preincubation of microsomes with 480156-S caused a concentration-dependent inhibition of CYP2C-dependent tolubutamide hydroxylation reaction in both rats and humans. There was a marked species difference in the susceptibility to the inhibitory effect of 480156-S, and the concentration required to inhibit rat CYP2C was almost 10 times higher than that required in humans. 5. The cephem antibiotics having N-methyltetrazolethiol (NMTT) at the 3'-position substituent were demonstrated to inhibit mitochondrial low K(m) aldehyde dehydrogenase (ALDH), and produced disulfiram-like (Antabuse) reaction during alcohol metabolism. Pharmacokinetic studies indicated that NMTT released from the antibiotics in bile duct or intestine cause the inhibitory action followed by the development of disulfiram-like reaction. 6. Attempts had been made to develop new cephem antibiotics lacking the disulfiram-like reaction by changing the chemical structure of 3'-position substituents, and a hydroxyethyltetrazolethiol was found not to inhibit the enzyme. Based on this result, together with the antibacterial activity, we have developed a new oxacephem antibiotic flomoxef (6315-S). Flomoxef showed no disulfiram-like reaction both in rats and human.
N-hydroxymethyl metabolites of 450191-S, a 1H-1,2,4,-triazolyl benzophenone derivative, in dog plasma
In a metabolic experiment of 5-[(2-aminoacetamido)methyl]-1-[4-chloro-2-(o-chlorobenzoyl)phenyl ]-N, N-dimethyl-1H-1,2,4,-triazole-3-carboxamide hydrochloride dihydrate (450191-S) in dogs, two new metabolites 8-chloro-6-(o-chlorophenyl)-N-hydroxymethyl-4H-1,2,4-triazolo [1,5-a] [1,4]benzodiazepine-2-carboxamide (M-A) and 8-chloro-6-(o-chlorophenyl)-N-hydroxymethyl-N-methyl-4H-1,2,4-triazolo [1,5-a] [1,4]benzodiazepine-2-carboxamide (M-D) in plasma were found in addition to 8-chloro-6-(o-chlorophenyl)-N,N-dimethyl-4H-1,2,4-triazolo[1,5-a] [1,4] benzodiazepine-2-carboxamide (M-1), 8-chloro-6-(o-chlorophenyl)-N-methyl-4H-1,2,4-triazolo[1,5-a] [1,4] benzodiazepine-2-carboxamide (M-2), 8-chloro-6-(o-chlorophenyl)-4H-1,2,4-triazolo-[1,5-a] [1,4] benzodiazepine-2-carboxamide (M-3), and 8-chloro-6-(o-chlorophenyl)-4H-1,2,4-triazolo[1,5-a] [1,4] benzodiazepine-2-carboxylic acid (M-4). The structures of N-hydroxymethyl metabolites were elucidated mainly by mass spectrometry. The structures were confirmed by synthesizing the authentic compounds and comparing the mass spectra.
Nocturnal enhancement of plasma melatonin could be suppressed by benzodiazepines in humans
Plasma melatonin levels were determined every 20 and 30 min for 24 hours on the last day of repeated oral administrations (1 or 2 mg a day for 8 or 9 days) of a benzodiazepine derivative (450191-s), which is known to be metabolized to active benzodiazepines after administration. In one of the two subjects, the nocturnal enhancement of plasma melatonin which was obvious on a control day with placebo was diminished almost completely. In the other subject, observed were not only the diminishment of its nocturnal enhancement but also its increase during the daytime almost to the nocturnal levels on a control day, which may indicate a rebound increase in melatonin synthesis or a shift in its day-night rhythmicity. Such suppressing effects of benzodiazepines on the nocturnal plasma melatonin levels were also examined in the case of a single administration of 2 mg of 450191-s or flunitrazepam in the second series of experiments. Even a single flunitrazepam seemed to have lowered nocturnal plasma melatonin levels, which then recovered to the usual levels following the administration of 5 mg of a benzodiazepine antagonist, Ro 15-1788, given 6 hours after the flunitrazepam. However, single 450191-s did not show any remarkable effects. Thus, it has been suggested that benzodiazepines could suppress the nocturnal levels of plasma melatonin or shift its day-night rhythmicity at least when administered repeatedly. The possible action site of benzodiazepines may be the central nervous system, since melatonin synthesis has been though to be under strongly regulated by the central nervous pathway from the retina to the pineal body. Therefore, these effects of benzodiazepines may provide a method for investigating the physiological role of melatonin and its day-night rhythmicity as well as to further clarify the system regulating melatonin synthesis in humans.
Effect of food on absorption of 450191-S, a 1H-1,2,4-triazolyl benzophenone derivative from rat small intestine
5-[(2-Aminoacetamide)methyl]-1-[p-chloro-2-(o-chlorobenzoyl)phenyl]- N, N-dimethyl-1 H-s-triazole-3-carboxamide hydrochloride dihydrate (450191-S), a newly synthesized sleep inducer, is a masked compound which is converted to 1,4-benzodiazepine by intestinal aminopeptidases during absorption from the small intestine. This study was an investigation on the effects of food on 450191-S pharmacokinetics. When 14C-450191-S was administered to non-fasted rats, peak plasma levels of total radioactivity were markedly reduced and its excretion into the bile was more delayed than when it was administered to fasted rats. One of the causes for these phenomena was thought to be a delayed absorption caused by the direct interaction between 450191-S and food in the intestinal lumen as well as the delayed gastric emptying rate. To confirm this interaction, we examined the effect of food on 450191-S uptake by the small intestine using rat everted jejunal sac in vitro. Subsequently, we found that the desglycylation of 450191-S was inhibited by rat food and that the uptake of 450191-S was reduced. In conclusion, 450191-S absorption is delayed by food, which results in the decreased total plasma level of 450191-S metabolites.