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Purity: ≥98%
| Targets |
The primary molecular target of INX 08189 is the HCV NS5B RNA-dependent RNA polymerase, an essential enzyme for viral replication. By inhibiting this polymerase, the compound prevents the synthesis of viral RNA, thereby halting the replication of the hepatitis C virus. Its activity is characterized by its potent EC50 values against various HCV genotypes, including 35 nM for genotype 1b in a standard 24-hour assay.
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| ln Vitro |
After 72 hours of exposure, BMS-986094 (INX-08189) has an EC50 of 10 nM against genotype 1b, 12 nM against genotype 1a, and an EC50 against genotype 2a, indicating that it is a highly strong inhibitor of HCV replication. 0.9 nanometers. In Huh-7 cells that have been grown, 7.01 μM is the concentration that results in 50% cytotoxicity (CC50) [1]. The luciferase activity in genotype 1b replicon cells is decreased in a concentration-dependent manner by BMS-986094 (5-80 nM; 14 days) [1]. For three days, BMS-986094 (20 μM) decreased the relative number of mitochondrial copies by 11% in CEM cells. Mitochondrial copy number in CEM cells is unaffected by BMS-986094 (1 μM; 14 days). In HepG2 cells, BMS-986094 does not change the relative amount of mitochondrial copy number [1]. In human hepatocytes (HH) and human cardiomyocytes (HCM), MS-986094 (10 µM; 24 hours) did not significantly raise the concentration of BMS-986094 or its metabolites, although INX-09114's intracellular concentration rose steadily at 7 After a year, it usually stabilizes. Incubate for one hour in HCM [3].
INX 08189 demonstrates highly potent in vitro activity against HCV replication. After 72 hours of exposure, it shows EC50 values of 10 nM against genotype 1b, 12 nM against genotype 1a, and 0.9 nM against genotype 2a, indicating its exceptional potency across multiple genotypes. In Huh-7 cells, it inhibits HCV replication with an EC50 of 35 nM at 24 hours. The compound functions as a potent inhibitor of the HCV NS5B polymerase, and its in vitro activity is a result of its intracellular conversion to the active triphosphate form. |
| ln Vivo |
After oral administration, BMS-986094 (3-300 mg/kg; po) is converted to 2'-C-Me-GTP, and the amount of 2'-C-MeG in plasma is proportionate to the amount of 2'-C-MeGTP produced in the liver [1]. In cynomolgus monkeys, oral administration of BMS-986094 (25 mg/kg) results in an effective extraction from the portal circulation via the liver [1]. Cynomolgus monkeys were given 15 or 30 mg/kg/d; po for three weeks; this was done using BMS-986094. The primary plasma analyte was the nucleoside metabolite M2, and the most drug-related species in the kidney and heart was INX-09114 [3].
While INX 08189 itself is a prodrug, its in vivo activity is derived from its active metabolite. After oral administration, it is efficiently extracted by the liver from the portal circulation. In preclinical models, it has shown potent antiviral efficacy against HCV. However, the compound was withdrawn from clinical trials due to serious safety issues, including cardiotoxicity. This highlights the importance of extensive safety evaluation, as a compound can be highly potent in vitro but have a narrow therapeutic window in vivo. |
| Enzyme Assay |
INX 08189 is a prodrug that requires metabolic activation. In vitro assays to study its mechanism often use liver microsomes or hepatocytes to assess its conversion to the active nucleotide. For direct NS5B polymerase inhibition, a cell-free assay using the purified enzyme and a template-primer is employed. The compound's inhibitory activity against the polymerase is determined by measuring the incorporation of labeled nucleotides into the growing RNA strand. For example, the inhibitory concentration (IC50) for the enzyme can be determined in such a system.
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| Cell Assay |
The in vitro antiviral activity of INX 08189 is typically assessed in cell-based replicon assays. In these assays, cells (such as Huh-7) stably expressing subgenomic HCV replicons are treated with the compound for a period, typically 24 to 72 hours. Viral replication is then quantified by measuring the levels of a reporter gene (e.g., luciferase) or HCV RNA. The effective concentration that reduces viral replication by 50% (EC50) is then calculated. This assay is the standard method for evaluating the potency of HCV inhibitors.
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| Animal Protocol |
Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat[1]
Doses: 3, 5, 10, 25 mg/kg Route of Administration: Single oral administration Experimental Results: 2′-C-MeGTP concentration at dose ≥5 mg/kg The liver exceeded the EC90 soon after administration and remained at or above this level for 72 hrs (hrs (hours)). The in vivo efficacy of INX 08189 was demonstrated in animal models of HCV infection, such as in chimeric mice with humanized livers. In these models, the compound was administered orally to evaluate its ability to reduce viral load. Pharmacokinetic and efficacy studies in crab monkeys showed that the liver effectively extracts the compound from the portal circulation after oral administration, indicating good oral bioavailability and hepatic targeting. Dosing typically involved oral administration of 25 mg/kg. |
| ADME/Pharmacokinetics |
INX 08189 is an orally bioavailable prodrug. Its pharmacokinetic profile is characterized by its absorption and metabolism. After oral administration, the phosphoramidate prodrug is efficiently absorbed and undergoes hepatic metabolism to release the active nucleotide monophosphate, which is then further phosphorylated to the active triphosphate. Preclinical studies indicated that the liver effectively extracts the compound from the portal circulation after oral administration, suggesting good hepatic targeting. The compound has a molecular weight of 658.64.
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| Toxicity/Toxicokinetics |
The development of INX 08189 was terminated due to serious adverse effects observed in clinical trials. The primary safety concern was cardiotoxicity, which led to its withdrawal from further development. This toxicity profile underscores the challenges in developing nucleoside analogs, where the active metabolites can sometimes have off-target effects on host cell machinery, particularly in tissues like the heart. The compound was evaluated in vitro for metabolism and reactive metabolite formation in human liver microsomes, hepatocytes, and cardiomyocytes.
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| References |
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| Additional Infomation |
INX-08189 has been used in therapeutic trials for hepatitis C, HCV (genotype 1), and hepatitis C virus.
INX 08189 is also known by the names BMS-986094, INX-189, and INX-08189. It is a phosphoramidate ProTide prodrug designed to deliver the nucleotide analog 6-O-methyl-2'-C-methyl guanosine monophosphate into cells. The compound was a clinical candidate for the treatment of chronic hepatitis C virus infection but was discontinued due to safety concerns. Its development was a collaborative effort, initially by Inhibitex and later by Bristol-Myers Squibb, as reflected in its name BMS-986094. |
| Molecular Formula |
C30H39N6O9P
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|---|---|
| Molecular Weight |
658.639
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| Exact Mass |
658.252
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| CAS # |
1234490-83-5
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| PubChem CID |
46700744
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| Appearance |
White to off-white solid powder
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| Density |
1.47
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| LogP |
3.671
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
13
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| Heavy Atom Count |
46
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| Complexity |
1100
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| Defined Atom Stereocenter Count |
5
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| SMILES |
C[C@@H](C(=O)OCC(C)(C)C)NP(=O)(OC[C@@H]1[C@H]([C@@]([C@@H](O1)N2C=NC3=C2N=C(N=C3OC)N)(C)O)O)OC4=CC=CC5=CC=CC=C54
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| InChi Key |
YFXGICNMLCGLHJ-RSKRLRQZSA-N
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| InChi Code |
InChI=1S/C30H39N6O9P/c1-17(26(38)42-15-29(2,3)4)35-46(40,45-20-13-9-11-18-10-7-8-12-19(18)20)43-14-21-23(37)30(5,39)27(44-21)36-16-32-22-24(36)33-28(31)34-25(22)41-6/h7-13,16-17,21,23,27,37,39H,14-15H2,1-6H3,(H,35,40)(H2,31,33,34)/t17-,21+,23+,27+,30+,46?/m0/s1
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| Chemical Name |
neopentyl
((((2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)-L-alaninate
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| Synonyms |
INX189 BMS986094 INX08189 INX 189 BMS-986094INX 08189INX-189 INX-08189 BMS 986094
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~250 mg/mL (~379.57 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.16 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.16 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5183 mL | 7.5914 mL | 15.1828 mL | |
| 5 mM | 0.3037 mL | 1.5183 mL | 3.0366 mL | |
| 10 mM | 0.1518 mL | 0.7591 mL | 1.5183 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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