SZM679 is an orally bioactive and selective RIPK1 inhibitor (antagonist) with Kds of 8.6 nM and >5000 nM for RIPK1 and RIPK3, respectively. SZM679 reverses tumor necrosis factor-induced systemic inflammatory response. SZM679 reduces Tau hyperphosphorylation, neuroinflammation, and RIPK1 phosphorylation levels in the hippocampus and cortex. SZM679 may be utilized in AD/Alzheimer's disease research.

Physicochemical Properties

Molecular Formula	C27H18F5N3O5S
Molecular Weight	591.51
CAS #	3027645-52-6
Appearance	Off-white to light yellow solid powder
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

Targets	RIPK1 8.6 nM (Kd) RIPK3 >5000 nM (Kd)
ln Vitro	SZM679 (0-10 μM; 24 h; necrotic L929 and HT-29 cells) inhibits the RIPK1 pathway with an EC50 value of 2 nM, which confers an anti-necrosis effect. Additionally, TNF-α, cycloheximide, and z-VAD-fmk(TCZ)-induced necroptosis are all prevented by SZM679. In a dose-dependent manner, SZM679 guards against TZ-induced necroptosis[1]. Necrotic HT-29 cells treated with SZM679 (1 μM; 6 h) preferentially suppresses RIPK1 expression but not RIPK3 or MLKL. SZM679 prevents the formation of necrosomes by preventing RIPK1 from being phosphorylated by TSZ[1].
ln Vivo	In vitro, SZM679 (10–40 mg/kg; ip; male C57BL/6 J mice with TNF-induced SIRS models) guards against TNF-induced systemic inflammatory response syndrome (SIRS) that is specific to necroptosis[1]. One daily for seven days, SZM679 (1 mg/kg) was injected intragastrically. enhances STZ-induced AD mice's cognitive function[1]. One daily for seven days, SZM679 (1 mg/kg) was injected intragastrically. reduces inflammatory cytokine expression, delays the onset of AD biomarkers, rescues brain structural damage without apparent toxicity, and prevents RIPK1 phosphorylation in AD mouse brain tissues[1].
Cell Assay	Western Blot Analysis[1] Cell Types: Necrotic HT-29 cells Tested Concentrations: 1 μM Incubation Duration: 6 hrs (hours) Experimental Results: Inhibited the phosphorylation of RIPK1 at 1 μM, resulting in the inhibition of the downstream phosphorylation of RIPK3 and MLKL.
Animal Protocol	Animal/Disease Models: Male C57BL/6 J mice with TNF-induced SIRS models[1] Doses: 10, 20, and 40 mg/kg Route of Administration: intraperitoneal (ip)injection Experimental Results: Protected mice in a dose-dependent manner from hypothermia and death. Animal/Disease Models: Male C57BL/6 J mice with AD models[1] Doses: 1 mg/kg Route of Administration: Administered intragastrically (po); one time/day for 7 days Experimental Results: Improved the anxiety, behavior, and exploratory ability of AD mice. Improved the learning and memory ability of AD mice. Animal/Disease Models: Male C57BL/6 J mice with AD models[1] Doses: 1 mg/kg Route of Administration: Administered intragastrically (po); one time/day for 7 days Experimental Results: Rescued the damaged hippocampal structure of AD mice and restored the cell number and morphology. Down-regulated the expression of the inflammatory cytokines, the IL-1β and TNF-α levels.
References	[1]. Discovery of a Trifluoromethoxy Cyclopentanone Benzothiazole Receptor-Interacting Protein Kinase 1 Inhibitor as the Treatment for Alzheimer's Disease. J Med Chem. 2022 Nov 10;65(21):14957-14969.

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	1.6906 mL	8.4529 mL	16.9059 mL
	5 mM	0.3381 mL	1.6906 mL	3.3812 mL
	10 mM	0.1691 mL	0.8453 mL	1.6906 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.