Clobazam is extensively metabolized in the liver via N-demethylation and hydroxylation to form two major metabolites, N-desmethylclobazam (norclobazam) and 4'-hydroxyclobazam, respectively. N-desmethylclobazam (norclobazam) retains pharmacological activity. Norclobazam is one-fourth the potency of clobazam. The main enzyme that facilitates the process of N-demethylation is CYP3A4, and to a lesser extent by CYP2C19 and CYP2B6. Norclobazam itself is also metabolized via hydroxylation, primarily by CYP2C19. The formation of 4'-hydroxyclobazam is facilitated by CYP2C18 and CYP2C19. A factor in determining extent of metabolism is the genetic profile of the individual patient as CYP2C19 is a polymorphic enzyme.
The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N-desmethylclobazam. In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers.
Clobazam is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug. The major metabolic pathway of clobazam involves N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3-5 times higher than those of the parent compound. Based on animal and in vitro receptor binding data, estimates of the relative potency of N-desmethylclobazam compared to parent compound range from 1/5 to equal potency. N-desmethylclobazam is extensively metabolized, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise approximately 94% of the total drug-related components in urine. Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.
A four-year-old male with symptomatic generalized epilepsy presented with ataxia, eye rolling, and episodes of back arching which were of non-epileptic origin following the introduction of clobazam at 0.75 mg/kg/day. Concurrent antiepileptic medication was lamotrigine at 13 mg/kg/day. Clobazam plasma levels were within the normal range, while N-desmethylclobazam (DCLB) concentrations were between five and seven times above the upper limit of the normal range. The plasma elimination half-life for DCLB was prolonged, suggesting a genetic variability in DCLB metabolism leading to toxicity. Reduction in the dose of clobazam to 0.3 mg/kg/day was associated with resolution of the non-epileptic neurological symptoms, reduction in DCLB plasma levels, and maintenance of seizure control.
来源:Hazardous Substances Data Bank (HSDB)
代谢
丁螺环酮已知的人类代谢物包括4-羟基丁螺环酮和N-去甲基丁螺环酮。
Clobazam has known human metabolites that include 4-Hydroxyclobazam and N-desmethylclobazam.
IDENTIFICATION AND USE: Clobazam is white to almost white, crystalline powder. Clobazam (DEA Code Number: 2751) is a Schedule IV controlled substance. It is used as anticonvulsant. HUMAN EXPOSURE AND TOXICITY: Overdose and intoxication with benzodiazepines, including clobazam, may lead to CNS depression, associated with drowsiness, confusion and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and, rarely, coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol. Serious and sometimes life-threatening dermatologic reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported rarely in both pediatric and adult patients treated with clobazam during postmarketing experience worldwide. Although such reactions may occur at any time during clobazam therapy, the risk is greater during the first 8 weeks of therapy or when clobazam is discontinued and then reinitiated. Physical and/or psychological dependence may occur in patients receiving clobazam. While the risk of dependence is greater with increasing dosage and duration of therapy, some patients can become physically or psychologically dependent even with short-term use of the drug (i.e., a few weeks) at recommended dosages. The risk of dependence also is increased in patients with a history of alcohol or substance abuse. As with all benzodiazepines, tolerance to the therapeutic effects of clobazam has been reported and may be a concern with long-term use of the drug. ANIMAL STUDIES: Signs exhibited during acute toxicity testing included somnolence, prostration, reduction in spontaneous motility, irregular breathing, ataxia, tremors, convulsions, loss of righting reflexes and reduction in body temperature. These were the most frequently observed signs in lethally poisoned animals. Clobazam was administered daily in the diet at doses of 0, 4, 20 and 100 mg/kg/day to groups of 60 male and 60 female rats for 104 weeks. Gross lesions identified at necropsy consisted of liver pallor and thyroid gland enlargement in males dosed at 100 mg/kg/day. The non-neoplastic histopathologic changes associated with treatment included an increased incidence of endometrial hyperplasia, cystic endometrial hyperplasia, and endometrial polyps and polypoid areas in females treated with 100 mg/kg/day. Thyroid changes included an increase in follicular cell adenomas in males (21.7% vs 5.7% in controls) treated with 100 mg/kg/day, and there was follicular carcinoma in one male (1.7%) of this group. One male rat in the 100 mg/kg/day group (1.7%) and one female rat in the 20 mg/kg/day (1.7%) group had squamous cell carcinomas in the thyroid gland. In the liver, changes included an increase in focal hyperplasia in females treated with 20 (11.7%) or 100 (6.7%) mg/kg/day. Nodular hyperplasias were increased in females treated with 100 mg/kg/day (3.3% vs 1.7% in controls). Hepatocellular carcinoma was found in one decedent female (1.7%) treated with 20 mg/kg/day. Clobazam was administered to Beagle dogs at doses of 0, 2.5, 5, 10, 20, 40 and 80 mg/kg for periods ranging from 6 to 12 months. Dose-dependent symptoms were noted and consisted of sedation, ataxia, mild tremors, somnolence, emesis, seizures and progressive rise in serum alkaline phosphatase. At the 80 mg/kg dose for 6 months a significant increase in the weight of the liver was observed in males and females. In the 12-month study using 0, 5, 10 and 40 mg/kg a dose-dependent increased accumulation of pigments in hepatocytes and Kupffer cells was observed in the 5 mg/kg group. In another 12-month study where 0, 2.5 and 5 mg/kg doses were used there were yellow granules in the epithelial cells of the proximal convoluted tubules in the 5 mg/kg group at one year. The studies have shown that convulsions were observed on the second and third day after abrupt discontinuation of the drug. In the one year study where 0, 5, 10 and 40 mg/kg of clobazam were used and in the 6-month study where 0, 5, 20 and 80 mg/kg were used, deaths occurred (9 and 2, respectively), but the exact cause could not be ascertained. However, the animals experienced convulsive seizures with foaming at the mouth during the treatment period. In rabbits, the rate of fetal resorption was higher in animals treated with 100 mg/kg than in the controls. In the group treated with 4 mg/kg, one unilateral exophthalmus, one exencephalus combined with ceolosomy and syndactyly of the front legs were observed, whilst in the 20 mg/kg group, one hydrocephalus with umbilical hernia was noted; these malformations were thought not to be drug related. Clobazam and the major active metabolite, N-desmethylclobazam, were negative for genotoxicity, based on data from a battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays.
Clobazam binds at distinct binding sites associated with the chloride ionopore at the post-synaptic GABA receptor. These GABA receptors are in various locations in the CNS (limbic, reticular formation) and clobazam increases the duration of time for which the chloride ionopore is open. As a result, hyper polarization and stabilization of the membrane occur as the post-synaptic inhibitory effect of GABA is enhanced.
Limited data are available on the hepatotoxicity of clobazam. In clinical trials, clobazam was not associated with an increased frequency of serum aminotransferase elevations as compared to placebo treatment, and there were no instances of clinically apparent liver injury. No individual case reports of clobazam hepatotoxicity have been published since its wide spread clinical availability. Liver injury from benzodiazepines is quite rare, but isolated instances of hepatotoxicity have been reported for clorazepate and clonazepam, two other benzodiazepines used predominantly in the therapy of epilepsy. Thus, clinically apparent liver injury due to clobazam must be rare, if it occurs at all.
来源:LiverTox
毒理性
致癌物分类
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
◉ Summary of Use during Lactation:Limited information indicates that maternal doses of clobazam up to 30 mg daily produce low levels in milk. Short-term use would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. During long-term administration, Monitor the infant for sedation, poor feeding and poor weight gain.
◉ Effects in Breastfed Infants:No adverse effects were reported in 10 newborns who were 4 to 23 days old who were breastfed during maternal intake of levetiracetam 1000 to 3000 mg daily. One mother was also taking tiagabine 30 mg daily, clobazam 45 mg daily and oxcarbazepine 600 mg daily.
The infants (including 3 preterm) of 18 nursing mothers who were taking levetiracetam and called the Pharmacovigilance Center in Lyon, France. One 25-day-old infant whose mother was taking levetiracetam 3000 mg daily plus clobazam was hospitalized for sedation, vomiting, and weight loss, and improved rapidly after breastfeeding discontinuation. Another infant exposed to levetiracetam and clobazam had poor weight gain, but it appeared to be caused by poor milk production.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
After oral administration of clobazam, it is almost completely absorbed (87% of dose). Bioavailability relative to solution was almost at 100%. Food does not affect absorption. Tmax = 1-3 hours.
来源:DrugBank
吸收、分配和排泄
消除途径
可乐定通过尿液以代谢物的形式消除（约94%）。
Clobazam is eliminated via the urine (~94%) as metabolites.
来源:DrugBank
吸收、分配和排泄
分布容积
Vdss = 100升。这个高的分布体积表明药物广泛分布到身体组织中。
Vdss = 100 L. This high volume of distribution suggests extensive distribution to body tissues.
Discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly
摘要：
The discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly is described. Synthesis of analogs of the 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hit established structure-activity relationships. Replacement of the enamine functionality of the hit series with either an imidazole or a pyrazole ring led to compounds that inhibited both capsid assembly and reverse transcriptase. Optimization of the bicyclic benzodiazepine scaffold to include a 3-phenyl substituent led to lead compound 48, a pure capsid assembly inhibitor with improved antiviral activity. (c) 2010 Elsevier Ltd. All rights reserved.
[EN] PROCESSES USEFUL FOR THE SYNTHESIS OF (R)-1-{2-[4'-(3-METHOXYPROPANE-1-SULFONYL)-BIPHENYL-4-YL]-ETHYL}-2-METHYL-PYRROLIDINE<br/>[FR] PROCÉDÉS UTILES POUR LA SYNTHÈSE DE LA (R)-1-{2-[4'-(3-MÉTHOXYPROPANE-1-SULFONYL)-BIPHÉNYL-4-YL]-ÉTHYL}-2-MÉTHYL-PYRROLIDINE
申请人：ARENA PHARM INC
公开号：WO2009128907A1
公开（公告）日：2009-10-22
Processes useful for making a pharmaceutically useful compound according to Formula (I), forms of such a compound, and intermediates useful in such processes are described.
根据公式（I）制备药用化合物的有用过程，以及该化合物的形式和在这些过程中有用的中间体被描述。
[EN] TREATMENT OF AUTISM SPECTRUM DISORDERS, OBSESSIVE-COMPULSIVE DISORDER AND ANXIETY DISORDERS<br/>[FR] TRAITEMENT DE TROUBLES DU SPECTRE AUTISTIQUE, DE TROUBLES OBSESSIVO-COMPULSIFS ET DE TROUBLES DE L'ANXIÉTÉ
申请人：RUGEN HOLDINGS CAYMAN LTD
公开号：WO2018098128A1
公开（公告）日：2018-05-31
Disclosed are methods for treating NMDA receptor-mediated disorders by administering certain NR2B subunit-selective NMDA (N methyl-D aspartate) antagonists. NMDA receptor-mediated disorders include autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders.
This invention relates to compounds of the formula (I):
wherein R
1
, R
2
, R
3
, A and m are each as described herein or a pharmaceutically acceptable salt or solvate thereof, and compositions containing such compounds and the use of such compounds in the treatment of a condition mediated by 5-HT
4
receptor activity such as, but not limited to, gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome.
