AzddMeC
(Synonyms: CS-92) 目录号 : GC65963AzddMeC (CS-92) 是一种抗病毒核苷类似物,也是一种有效的,选择性的,具有口服活性的 HIV-1 逆转录酶和 HIV-1 复制的抑制剂。在感染 HIV-1 的人类 PBM 细胞和感染 HIV-1 的人类巨噬细胞中,AzddMeC 的 EC50 值分别为 9 nM 和 6 nM。
Cas No.:87190-79-2
Sample solution is provided at 25 µL, 10mM.
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AzddMeC (CS-92) is an antiviral nucleoside analogue and a potent potent, selective and orally active HIV-1 reverse transcriptase and HIV-1 replication inhibitor. In HIV-1-infected human PBM cells and HIV-1-infected human macrophages, the EC50 values of AzddMeC are 9 nM and 6 nM, respectively[1][2].
AzddMeC (CS-92) is also effective against HIV-2 in lymphocytes. The replication of Friend murine virus is only weakly inhibited, and no effect is observed against HSV type 1 and type 2 and coxsackievirus B4. The interaction of the 5'-triphosphate of AzddMeC with HIV-1 reverse transcriptase indicated competitive inhibition (the inhibition constant, Kis, is 9.3 nM)[1].
The pharmacokinetics of AzddMeC are characterized following intravenous and oral administration of 60 mg/kg of the compound to male rhesus monkeys. 3'-azido-3'-deoxythymidine (AZT) is a major metabolite of AzddMeC in monkeys. AzddMeC concentrations in serum declined rapidly in a biexponential fashion with the terminal half-life ranging from 0.5 to 1.3 hr. Renal excretion of unchanged nucleoside and metabolic deamination yielding AZT are the primary routes of AzddMeC clearance. The oral bioavailability is 26%[2].
Cas No. | 87190-79-2 | SDF | Download SDF |
别名 | CS-92 | ||
分子式 | C10H14N6O3 | 分子量 | 266.26 |
溶解度 | DMSO : 200 mg/mL (751.15 mM; Need ultrasonic) | 储存条件 | 4°C, away from moisture |
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10 mM | 0.3756 mL | 1.8779 mL | 3.7557 mL |
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Pharmacokinetics and metabolism of 3'-azido-2',3'-dideoxy-5-methylcytidine in rhesus monkeys
Drug Metab Dispos 1993 Sep-Oct;21(5):855-60.PMID:7902248doi
3'-Azido-2',3'-dideoxy-5-methylcytidine (AzddMeC, CS-92), a nucleoside analog with structural similarities to both 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC), has been shown to be a potent and selective inhibitor of human immunodeficiency virus type 1 in vitro. The pharmacokinetics of AzddMeC were characterized following intravenous and oral administration of 60 mg/kg of the compound to male rhesus monkeys. AZT was found to be a major metabolite of AzddMeC in monkeys. AzddMeC concentrations in serum declined rapidly in a biexponential fashion with the terminal half-life ranging from 0.5 to 1.3 hr. Total clearance of AzddMeC was 2.00 +/- 0.41 liters/hr/kg (mean +/- SD) with the fraction of AzddMeC metabolized to AZT of 0.32 +/- 0.05. Renal excretion of unchanged nucleoside and metabolic deamination yielding AZT were the primary routes of AzddMeC clearance. No glucuronide metabolite of AzddMeC was detected in urine samples, although, AZT-glucuronide was found in urine. The volume of the central compartment of AzddMeC was 0.53 +/- 0.28 liters/kg, the volume of the tissue compartment was 0.37 +/- 0.29 liters/kg, and the steady-state volume of distribution was 0.90 +/- 0.55 liters/kg. Volume of distribution values indicate that AzddMeC distributes extravascularly. The first-order oral absorption rate constant was 0.53 +/- 0.56 hr-1, and oral bioavailability was 26 +/- 13%. Thus, the rate of absorption of AzddMeC after oral administration was variable, and oral bioavailability was incomplete.
Antiretroviral activity, biochemistry, and pharmacokinetics of 3'-azido-2',3'-dideoxy-5-methylcytidine
Ann N Y Acad Sci 1990;616:385-97.PMID:1706574DOI:10.1111/j.1749-6632.1990.tb17858.x.
3'-Azido-2',3'-dideoxy-5-methylcytidine (CS-92, AzddMeC) is an antiviral nucleoside analogue structurally related to 3'-azido-3'-deoxythymidine (AZT). CS-92 is a potent and selective inhibitor of HIV-1 reverse transcriptase and HIV-1 replication in human lymphocytes and macrophages. The EC50 for CS-92 in HIV-1-infected human PBM cells was 0.09 microM. In HIV-1-infected human macrophages, the EC50 was 0.006 microM. This compound was also effective against human immunodeficiency virus type 2 in lymphocytes. The replication of Friend murine virus was only weakly inhibited, and no effect was observed against herpes simplex virus type 1 and type 2 and coxsackievirus B4. CS-92 was not toxic to PBM or Vero cells when tested up to 200 microM and was, furthermore, at least 40 times less toxic to granulocyte-macrophage and erythroid precursor cells in vitro than was AZT. The interaction of the 5'-triphosphate of CS-92 with HIV-1 reverse transcriptase indicated competitive inhibition (the inhibition constant, Kis, was 0.0093 microM) with a 30-fold greater affinity for CS-92-TP than for ddCTP. CS-92-TP inhibited HIV-1 reverse transcriptase by 50% at a concentration 6,000-fold lower than that which was required for a similar inhibition of DNA polymerase alpha. Pharmacokinetic studies showed that CS-92 was not deaminated to AZT in rats, but this compound was found to have a half-life of 2.7 hours. In rhesus monkeys, however, a compound with a retention time and ultraviolet spectra characteristics similar to AZT was detected. The mean half-life in rhesus monkeys for CS-92 was 1.52 and 1.74 h after intravenous and oral administration, respectively, and the oral bioavailability was about 21 percent. Additional preclinical studies with CS-92 will determine the ultimate utility of this antiviral agent for the treatment of HIV-1 infections.
Catabolic disposition of 3'-azido-2',3'-dideoxyuridine in hepatocytes with evidence of azido reduction being a general catabolic pathway of 3'-azido-2',3'-dideoxynucleosides
Biochem Pharmacol 1992 Sep 1;44(5):973-80.PMID:1326966DOI:10.1016/0006-2952(92)90130-b.
3'-Azido-2',3'-dideoxyuridine (AzddU, CS-87) is a potent inhibitor of human immunodeficiency virus replication in vitro with low bone marrow toxicity. Although AzddU is currently being evaluated in clinical trials, its catabolic disposition is unknown. Pharmacokinetic studies in rhesus monkeys have demonstrated that a 5'-O-glucuronide is excreted in urine. The present study examined the catabolic disposition of AzddU is isolated rat hepatocytes, a model for the study at the cellular level of biosynthetic, catabolic and transport phenomena in the liver. Following exposure of cells to 10 microM [3H]AzddU, low intracellular levels of two catabolites, identified as 3'-azido-2',3'-dideoxy-5'-beta-D-glucopyranosyluridine (GAzddU) and 3'-amino-2',3'-dideoxyuridine (AMddU), were detected. Studies using rat microsomes demonstrated that GAzddU formation was only detected in the presence of uridine 5'-diphosphoglucuronic acid, and that the rate of AMddU formation increased significantly in the presence of NADPH. Under similar conditions, reduction of the 3'-azido function was also demonstrated herein with 3'-azido-2',3'-dideoxycytidine (AzddC), 3'-azido-2',3'-dideoxy-5-methylcytidine (AzddMeC) and 3'-azido-2',3'-dideoxyguanine (AzddG), suggesting that enzymatic reduction to a 3'-amino derivative is a general catabolic pathway of 3'-azido-2',3'-dideoxynucleosides at the hepatic site.