SR 1903

Product NameSR 1903
CAS1414248-06-8
MFC27H27F6N3O
MW523.52
EINECS
MOL File1414248-06-8.mol

Chemical Properties

Boiling point	559.0±50.0 °C(Predicted)
Density	1.307±0.06 g/cm3(Predicted)
storage temp.	Store at -20°C
solubility	DMF: 20 mg/ml; DMSO: 20 mg/ml; Ethanol: 10 mg/ml
form	A crystalline solid
pka	9.23±0.15(Predicted)

Usage And Synthesis

Description

SR-1903 is a modulator of retinoic acid receptor-related orphan receptor γ (RORγ) and liver X receptor (LXR). It is an inverse agonist of RORγ and an agonist of LXR. It also binds to peroxisome proliferator-activated receptor γ (PPAR) but does not activate it. SR-1903 inhibits LPS-induced expression of triggering receptor expressed on myeloid cells 1 (TREM-1). It also inhibits LPS-induced expression of the LXR target genes IL-6 and IL-33 and increases expression of ABCG1, FASN, and SCD-1. SR-1903 reduces the severity of collagen-induced arthritis. It reduces blood glucose levels in a glucose tolerance test, serum levels of total cholesterol and LDL, body weight, and fat mass in a mouse model of high-fat diet-induced obesity.

Uses

SR-1903 is an inverse agonist of RORγ and PPARγ (IC50 of ～100 nM and 209 nM for RORγ and PPARγ, respectively) and a LXR agonist. SR-1903 exhibits anti-inflammatory and anti-diabetic efficacy in collagen-induced arthritis and diet-induced obesity mouse models[1].

in vivo

SR1903 (20 mg/kg, i.p., twice-a-day for a total of 16 days) ameliorates arthritic symptoms and prevents thymocyte loss in collagen-induced arthritis (CIA) mice^[1].
SR1903 (20 mg/kg, i.p., 14 days) improves metabolic parameters and protects against obesity-associated thymic degeneration in diet-induced obese (DIO) mice^[1].

Animal Model:	Collagen-induced arthritis (female DBA/1J mice were injected with chicken type II collagen on day 1, and then each animal received a boost injection of collagen on day 21)^[1]
Dosage:	20 mg/kg
Administration:	Intraperitoneal injection (i.p.), twice-a-day for a total of 16 days
Result:	Demonstrated a reduction in arthritis clinic score at the conclusion of the study (day 34). Did not cause enlargement of the liver. Had enhanced thymocyte differentiation and survival compared to mice treated with either the selective LXR agonist GW3965 or the dual LXR agonist/RORγ inverse agonist T0901317.

Animal Model:	Diet-induced obese (DIO) mouse (Male, 22 weeks of age, fed a high fat diet (60% kCal % fat))^[1]
Dosage:	20 mg/kg
Administration:	Intraperitoneal injection (i.p.), 14 days
Result:	Improved fasting glucose levels and reduced total cholesterol and low density lipoprotein (LDL). Improved both fasting and fed insulin levels. Showed 15% weight loss and 17% reduction in fat mass after 14 days. Reduced food intake. Reduced leptin resistance and repressed Socs3 (suppressor of cytokine signaling-3) expression.

IC 50

RORγ: ~100 nM (IC₅₀); PPARγ: 209 nM (IC₅₀)

References

[1] Chang MR, et al. Unique Polypharmacology Nuclear Receptor Modulator Blocks Inflammatory Signaling Pathways. ACS Chem Biol. 2019, 14(5):1051-1062. DOI:10.1021/acschembio.9b00236

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