BMS-986163, a novel water-soluble phosphate prodrug of BMS-986169 designed for IV administration, is a negative allosteric modulator of GluN2B which is a N-methyl-d-aspartate receptor subtype. The prodrug BMS-986163 can be rapidly convertd to its active form BMS-986169 which has Ki of 4 nM and IC50 of 24 nM. BMS-986163 has potential to be used in major depressive disorder. BMS-986169 exhibited high binding affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug BMS-986163 to parent BMS-986169 was rapid in vitro and in vivo across preclinical species. The prodrug BMS-986163 has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.
Physicochemical Properties
| Molecular Weight | 462.45099067688 |
| Exact Mass | 462.171 |
| CAS # | 1801151-09-6 |
| Related CAS # | 1801151-09-6; 1801151-08-5; |
| PubChem CID | 91820629 |
| Appearance | Typically exists as solid at room temperature |
| LogP | 0.2 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 32 |
| Complexity | 690 |
| Defined Atom Stereocenter Count | 3 |
| SMILES | CC1=CC=C(C=C1)CN2CC[C@H](C2=O)N3CC[C@H]([C@@H](C3)F)C4=CC=C(C=C4)OP(=O)(O)O |
| InChi Key | ZPUVTBAQHJFPHE-BHDDXSALSA-N |
| InChi Code | InChI=1S/C23H28FN2O5P/c1-16-2-4-17(5-3-16)14-26-13-11-22(23(26)27)25-12-10-20(21(24)15-25)18-6-8-19(9-7-18)31-32(28,29)30/h2-9,20-22H,10-15H2,1H3,(H2,28,29,30)/t20-,21+,22+/m0/s1 |
| Chemical Name | 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate |
| Synonyms | Prodrug of BMS-986169; BMS-986163; BMS 986163; BMS986163. |
| 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) |
Biological Activity
| ln Vivo |
the dihydrogen phosphate BMS-986163 exhibited optimal properties for an intravenous agent. The prodrug was a zwitterionic monohydrate with a sharp melting point of 172 °C. Crystalline material had aqueous solubility of 19.9 mg/mL at pH 7.4. The prodrug was physically and chemically stable in the solid state at 50 °C for up to 4 weeks. Aqueous solutions of 6 were stable for up to 90 days at 25 °C. The prodrug itself demonstrated no relevant in vitro biological activity. Prodrug to parent conversion was rapid in rat, monkey, dog, and human blood at 37 °C. After i.v. administration of prodrug 6 (1.2 mg/kg) in Cynomolgous monkey, prodrug concentrations in the plasma were undetectable 10 min postdose, and the plasma AUCtotal exposure of active parent 5 was approximately 63% of that observed from direct administration of 5 (1.0 mg/kg, i.v.).26 The loss in exposure was not accounted for, but it may be attributed to metabolism of the prodrug prior to phosphate cleavage. Exposure data for the metabolites met-1 and met-2 was collected in the monkey PK study. The carboxylic acid met-1 displayed a plasma AUCtotal that was 36% of parent 5 and AUCtotal for the lactam met-2 was 130% of parent. While in vivo conversion of prodrug to parent was not quantitative, the high solubility of 6 and its rapid conversion to 5 supported additional in vivo studies and dose escalating toxicology experiments. Specific to on-target pharmacology, the prodrug 6 produced robust levels of ex vivo GluN2B receptor occupancy in rat, in vivo functional inhibition of [3H]MK-801 binding in rat, and dose-dependent activity in novelty-suppressed feeding (NSF) in mice after i.v. dosing. The safety and tolerability of BMS-986163 was evaluated in two studies. In a 4-day rat experiment, where prodrug 6 was dosed at 10, 30, and 100 mg/kg/day (i.v.), there were no significant clinical-pathological and histopathological observations at any dose. An average total plasma exposure of parent 5 in excess of 48 μM·h was observed at day 4 for the 100 mg/kg/day dose group. In a monkey single-dose toxicokinetic tolerability study at 3.6, 12, and 36 mg/kg (i.v.), all doses were well tolerated with no significant drug related effects. The high dose group exhibited an average Cmax = 19 μM and total plasma AUC24 = 88 μM·h for parent 5.[1] |
| References | ACS Med Chem Lett. 2018 Apr 13;9(5):472-477. |
Solubility Data
| 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 (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *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). 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)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL 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). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1624 mL | 10.8120 mL | 21.6240 mL | |
| 5 mM | 0.4325 mL | 2.1624 mL | 4.3248 mL | |
| 10 mM | 0.2162 mL | 1.0812 mL | 2.1624 mL |