Otaplimastat (SP-8203) is a novel and potent MMP/matrix metalloproteinase inhibitor with anti-oxidant and neuroprotective activity. It inhibits matrix metalloprotease pathway, and reduces edema and intracerebral hemorrhage induced by recombinant tissue plasminogen activator (rtPA) in animal stroke models. Otaplimastat also blocks N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity in a competitive manner. Otaplimastat also exhibits anti-oxidant activity. Otaplimastat may be used for brain ischemic injury.
Physicochemical Properties
| Molecular Formula | C28H34N6O5 |
| Molecular Weight | 534.61 |
| Exact Mass | 534.259 |
| CAS # | 1176758-04-5 |
| PubChem CID | 44229378 |
| Appearance | Off-white to light yellow solid powder |
| Density | 1.3±0.1 g/cm3 |
| Index of Refraction | 1.589 |
| LogP | 1.76 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 13 |
| Heavy Atom Count | 39 |
| Complexity | 913 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | SJZBPVOSFYUHFV-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C28H34N6O5/c1-20(35)32(17-9-19-34-26(37)22-11-3-5-13-24(22)31-28(34)39)16-7-6-14-29-15-8-18-33-25(36)21-10-2-4-12-23(21)30-27(33)38/h2-5,10-13,29H,6-9,14-19H2,1H3,(H,30,38)(H,31,39) |
| Chemical Name | N-[3-(2,4-dioxo-1H-quinazolin-3-yl)propyl]-N-[4-[3-(2,4-dioxo-1H-quinazolin-3-yl)propylamino]butyl]acetamide |
| Synonyms | SP8203 SP-8203Otaplimastat |
| 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 Vitro | In a competitive way, otaplimastat (87.5-350 μM; 20 min) shields neuronal cells against NMDA-induced cell death[1]. In primary cultured neurons, otaplimastat (350 μM) decreases Ca2+ influx after NMDA receptor activation[1]. Reactive oxygen species generation and H2O2-induced cell death are greatly suppressed by otaplimastat (200–200 μM; pretreated for 4 hours)[2]. |
| ln Vivo | In the occlusion model of MCA, otaplimastat (10–20 mg/kg; ip 30 min before occlusion and 1 h after reperfusion) reduces ischemic neuronal death[1]. Otaplimastat (5–10 mg/kg; intraperitoneally; i.p. daily for 10 days) reduces impairment of motor function caused by stroke[2]. |
| Animal Protocol |
Animal/Disease Models: Male Wistar rats (280-310 g, 9 weeks) were induced transient middle cerebral artery (MCA) occlusion[1] Doses: 10, 20 mg/kg Route of Administration: Ip before 30 min and after an hour of the MCA-occlusion operation Experimental Results: Dramatically decreased infarct volume. Improved spatial learning and memory impairments. |
| References |
[1]. SP-8203 shows neuroprotective effects and improves cognitive impairment in ischemic brain injury through NMDA receptor. Pharmacol Biochem Behav. 2011 Nov;100(1):73-80. [2]. SP-8203 reduces oxidative stress via SOD activity and behavioral deficit in cerebral ischemia. Pharmacol Biochem Behav. 2011 Mar;98(1):150-4. [3]. Safety and Efficacy of Otaplimastat in Patients with Acute Ischemic Stroke Requiring tPA (SAFE-TPA): A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Study. Ann Neurol. 2020 Feb;87(2):233-245. |
| Additional Infomation | SP-8203 has been used in trials studying the treatment of Ischemic Stroke. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~187.05 mM) |
| 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 | 1.8705 mL | 9.3526 mL | 18.7052 mL | |
| 5 mM | 0.3741 mL | 1.8705 mL | 3.7410 mL | |
| 10 mM | 0.1871 mL | 0.9353 mL | 1.8705 mL |