2. MAPK/ERK Pathway NF-κB Metabolic Enzyme/Protease Immunology/Inflammation
  3. p38 MAPK Keap1-Nrf2 Reactive Oxygen Species (ROS)
  4. SH494

SH494 is a p38 MAPK inhibitor and Nrf2 pathway activator. SH494 inhibits RANKL-induced phosphorylation of p38 and disrupts the MAPK cascade associated with osteoclastogenesis. SH494 activates the Nrf2 pathway, upregulates downstream target genes and induces the expression of cytoprotective enzymes. SH494 reduces intracellular ROS accumulation and restores mitochondrial membrane potential (ΔΨm) to normal. SH494 decreases osteoclast activity and alleviates osteoporosis symptoms in ovariectomized mice. SH494 can be used for research on osteoporosis.

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SH494

SH494 Chemical Structure

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SH494 Related Antibodies

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p38 MAPK Akt1 p38α p38β MAPK13 p38δ p38γ

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Description

SH494 is a p38 MAPK inhibitor and Nrf2 pathway activator. SH494 inhibits RANKL-induced phosphorylation of p38 and disrupts the MAPK cascade associated with osteoclastogenesis. SH494 activates the Nrf2 pathway, upregulates downstream target genes and induces the expression of cytoprotective enzymes. SH494 reduces intracellular ROS accumulation and restores mitochondrial membrane potential (ΔΨm) to normal. SH494 decreases osteoclast activity and alleviates osteoporosis symptoms in ovariectomized mice. SH494 can be used for research on osteoporosis[1].

In Vitro

SH494 (0.01-1 μM; 7 days) potently inhibits RANKL-induced osteoclast differentiation in mouse bone marrow macrophages (BMMs), with an IC50 of 8.4 nM, and achieves complete inhibition at concentrations ≥0.1 μM following 7 days of treatment[1].
SH494 (0.01-1 μM; 7 days) dose-dependently inhibits RANKL-induced F-actin ring formation in mouse bone marrow macrophages (BMMs)[1].
SH494 (0.01-1 μM; 1-5 days) dose-dependently and time-dependently downregulates the mRNA expression of key osteoclastogenic genes in mouse bone marrow macrophages (BMMs) treated with RANKL and M-CSF[1].
SH494 (0.01-1 μM; 72 h) dose-dependently inhibits the protein expression of key osteoclastogenic markers (c-Fos, Ctsk, Mmp9) in mouse bone marrow-derived macrophages (BMMs)[1].
SH494 (1 μM; 5-30 min) inhibits RANKL-induced phosphorylation of p38 MAPK in mouse bone marrow macrophages (BMMs) at 5, 10, and 30 min following RANKL stimulation[1].
SH494 (0.01-1 μM; 48-72 h) reduces RANKL-induced ROS accumulation in mouse bone marrow macrophages (BMMs) and restores their mitochondrial membrane potential after 48 h; meanwhile, it activates the Nrf2 pathway by upregulating the expression of Cat, Gclc and HO-1, as well as increasing the nuclear localization of Nrf2[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

SH494 Related Antibodies

Real Time qPCR[1]

Cell Line: mouse bone marrow-derived macrophages (BMMs)
Concentration: 0.01 μM (48 h), 0.1 μM (48 h), 1 μM (48 h; 1, 3, 5 days)
Incubation Time: 48 h (concentration-dependent analysis); 1, 3, 5 days (time course with 1 μM SH494)
Result: Dose-dependently downregulated the mRNA expression of key osteoclastogenic markers: Nfatc1, Trap, Ctsk, Mmp9, and c-Fos after 48 h.
Over a 5-day time course, 1 μM SH494 abrogated RANKL-induced upregulation of Nfatc1, Trap, Ctsk, and c-Fos throughout differentiation.

Western Blot Analysis[1]

Cell Line: mouse bone marrow-derived macrophages (BMMs)
Concentration: 0.01 μM, 0.1 μM, 1 μM
Incubation Time: 72 h
Result: Dose-dependently reduced the protein levels of c-Fos, Ctsk, and Mmp9 in RANKL-stimulated BMMs.

Western Blot Analysis[1]

Cell Line: mouse bone marrow-derived macrophages (BMMs)
Concentration: 1 μM
Incubation Time: pretreated, then incubated with RANKL for 5, 10, 30 min
Result: Markedly inhibited RANKL-induced phosphorylation of p38 at all tested time points.
Parmacokinetics
Species Dose Route Tmax Cmax AUC0-t AUC0-∞ Vz CL T1/2 F
Mice[1] 1.0 mg/kg i.v. 0.083 h 1093 ng/mL 396 ng·h/mL 399 ng·h/mL 674 mL/kg 42 mL/min/kg 0.32 h /
Mice[1] 10.0 mg/kg p.o. 0.333 h 1162 ng/mL 1061 ng·h/mL 1067 ng·h/mL / / 0.66 h 26.8 %
In Vivo

SH494 (1-5 mg/kg; i.p.; once daily; 6 weeks) dose-dependently prevents ovariectomy-induced bone loss in mice[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: C57BL/6 (8-week-old female; osteoporosis induced by bilateral ovariectomy)[1]
Dosage: 1 mg/kg; 5 mg/kg
Administration: i.p.; once daily; 6 weeks
Result: Increased bone volume fraction (BV/TV) by 40.66%, trabecular number (Tb.N) by 28.35%, and bone surface density (BS/TV) by 33.43% relative to vehicle-treated OVX mice at 5 mg/kg.
Dose-dependently prevented OVX-induced bone microstructural deterioration, with the 5 mg/kg dose showing improvement in Tb.N and BS/TV comparable to positive control teriparatide.
Preserved trabecular architecture and reduced osteoclast numbers in treated groups.
Showed no systemic or organ-specific toxicity, with stable body weights and normal histology of major organs.
Molecular Weight

494.63

Formula

C31H34N4O2
SMILES

C[C@]12[C@]([H])([C@@]3(CCC4=CC(CC[C@@]4(C3=CC2)C)=O)[H])CC(C1=NC5=NC=NN65)=C6C7=CC=C(C=C7)OCCC
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Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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SH494 Related Classifications

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Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

SH494SH 494SH-494p38 MAPKKeap1-Nrf2Reactive Oxygen Species (ROS)TraposteoclastogenesisNfatc1CtskRANKLc-FosNrf2 pathwayMmp9mouse BMMsInhibitorinhibitorinhibit

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