| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
NS5B polymerase; hepatitis C virus
|
|---|---|
| ln Vitro |
The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as XimencyTM. [1]
The methyl-substituted cyclopropyl acylsulfonamide 17/BMS-961955 exhibited potency comparable to both 1 and 3 against GT 1a and 1b replicons with EC50 values of 4 nM and 7 nM, respectively. The EC50 value of 17/BMS-961955 toward GT 1a increased by 8.2-fold in the presence of 40% human serum, indicative of a minimal effect. Compound 17 potently and specifically inhibited the HCV NS5B polymerase derived from HCV GT 1, and GTs 3–6, with IC50 values of 4 nM (1a), 5 nM (1b), 2 nM (3a), 44 nM (4a), 15 nM (5a) and 124 nM (6a) while GT 2 NS5B was found to be less susceptible with IC50 values of 597 nM (2a) and 212 nM (2b). Compound 17 displayed significantly enhanced metabolic stability in CLM and HLM when compared to 1 and it was not an inhibitor of recombinant CYP isoforms in HLM. In addition, no evidence of CYP induction was observed in human hepatocytes [1]. |
| ADME/Pharmacokinetics |
Compound 17/BMS-961955 exhibited high permeability in a PAMPA assay with Pc values of 523 nm/s at pH 5.5 and 590 nm/s at pH 7.4 and also displayed excellent PK properties in the rat, dog and cynomolgus monkey (Table 3). Clearance was low to moderate across the species while the volume of distribution and half-life values were moderate and bioavailability ranged from 48 to 84%. The predicted human dose based on the replicon potency and 3-species PK was 70 mg once a day (QD). [1]
|
| Toxicity/Toxicokinetics |
As a result of its excellent potency, clean preclinical profile and excellent QD dosing potential, 17/BMS-961955 was advanced into a two week toxicology study in rats. No significant liabilities or issues were identified with only minimal findings at adequate exposure margins. A two week toxicology study in dogs was used to determine that 17 had a toxicology safety profile that supported advancement and clearly differentiated this compound from 3. However, further development of 17 was not pursued based on the successful continued development of beclabuvir.
|
| References |
[1]. Discovery of BMS-961955, an allosteric inhibitor of the hepatitis C virus NS5B polymerase. Bioorg Med Chem Lett. 2017 Aug 1;27(15):3294-3300
|
| Additional Infomation |
In conclusion, after the discovery of compound 17/BMS-961955, preclinical profiling showed that the compound was a metabolically-stable HCV NS5B thumb site 1 inhibitor with a low projected human dose for the potential treatment of GT 1 HCV viruses and the compound was accepted as a candidate for development. Inhibitor 17 has two regions of structural differentiation from the beclabuvir (1), both located at sites of metabolic modification. However, the ultimately successful progression of 1 in clinical development eventually obviated further advancement of 17. [1]
|
| Molecular Formula |
C37H43FN4O4S
|
|---|---|
| Molecular Weight |
658.83
|
| Exact Mass |
658.298
|
| Elemental Analysis |
C, 67.45; H, 6.58; F, 2.88; N, 8.50; O, 9.71; S, 4.87
|
| CAS # |
1431328-92-5
|
| PubChem CID |
71548918
|
| Appearance |
Typically exists as solid at room temperature
|
| Density |
1.5±0.1 g/cm3
|
| Index of Refraction |
1.751
|
| LogP |
5.97
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
47
|
| Complexity |
1380
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
S(C1(C)CC1)(NC(C1C=CC2C(C3CCCCC3)=C3C4C=CC(=CC=4[C@@H]4C[C@]4(C(N4C5CN(C)CC4CC5)=O)CN3C=2C=1)F)=O)(=O)=O
|
| InChi Key |
CWSDSHIYVCDQNB-CYOAQLCUSA-N
|
| InChi Code |
InChI=1S/C37H43FN4O4S/c1-36(14-15-36)47(45,46)39-34(43)23-8-12-28-31(16-23)41-21-37(35(44)42-25-10-11-26(42)20-40(2)19-25)18-30(37)29-17-24(38)9-13-27(29)33(41)32(28)22-6-4-3-5-7-22/h8-9,12-13,16-17,22,25-26,30H,3-7,10-11,14-15,18-21H2,1-2H3,(H,39,43)/t25?,26?,30-,37-/m0/s1
|
| Chemical Name |
(8S,10R)-19-cyclohexyl-5-fluoro-N-(1-methylcyclopropyl)sulfonyl-10-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-12-azapentacyclo[10.7.0.02,7.08,10.013,18]nonadeca-1(19),2(7),3,5,13(18),14,16-heptaene-15-carboxamide
|
| Synonyms |
BMS-961955; BMS 961955; CHEMBL4067852; SCHEMBL14876746; 1431328-92-5; BDBM50268397; (8S,10R)-19-cyclohexyl-5-fluoro-N-(1-methylcyclopropyl)sulfonyl-10-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-12-azapentacyclo[10.7.0.02,7.08,10.013,18]nonadeca-1(19),2(7),3,5,13(18),14,16-heptaene-15-carboxamide; BMS961955
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5178 mL | 7.5892 mL | 15.1784 mL | |
| 5 mM | 0.3036 mL | 1.5178 mL | 3.0357 mL | |
| 10 mM | 0.1518 mL | 0.7589 mL | 1.5178 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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