RS504393

• CAT Number: I003044
• CAS Number: 300816-15-3
• Molecular Formula: C25H27N3O3
• Molecular Weight: 417.5
• Purity: ≥95%
• Synonyms: RS 504393; 6-Methyl-1′-(2-(5-methyl-2-phenyloxazol-4-yl)ethyl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one; RS-504393; RS504393
• Target: CCR2
• Solubility: 10 mM in DMSO
• Storage: Store at -20°C
• IC50: 98 nM
• IUPAC Name: 6-methyl-1'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl]spiro[1H-3,1-benzoxazine-4,4'-piperidine]-2-one
• InChI: InChI=1S/C25H27N3O3/c1-17-8-9-22-20(16-17)25(31-24(29)27-22)11-14-28(15-12-25)13-10-21-18(2)30-23(26-21)19-6-4-3-5-7-19/h3-9,16H,10-15H2,1-2H3,(H,27,29)
• InChIKey: ODNICNWASXKNNQ-UHFFFAOYSA-N
• SMILES: CC1=CC2=C(C=C1)NC(=O)OC23CCN(CC3)CCC4=C(OC(=N4)C5=CC=CC=C5)C

RS504393(CAT: I003044) is a small molecule inhibitor of the C-C chemokine receptor type 2 (CCR2). CCR2 is a chemokine receptor that is involved in the recruitment of inflammatory cells to sites of tissue injury and inflammation. Inhibition of CCR2 is a potential therapeutic strategy for a variety of inflammatory and autoimmune diseases. RS504393 has been shown to block the binding of monocyte chemoattractant protein-1 (MCP-1) to CCR2 and to reduce the recruitment of monocytes and macrophages to sites of inflammation in animal models. It has been studied as a potential treatment for a range of inflammatory conditions, including rheumatoid arthritis, atherosclerosis, and multiple sclerosis.

Reference

1. J Neuroimmune Pharmacol. 2017 Sep;12(3):402-419. doi: 10.1007/s11481-017-9729-6.
Epub 2017 Mar 23.

The RS504393 Influences the Level of Nociceptive Factors and Enhances Opioid
Analgesic Potency in Neuropathic Rats.

Kwiatkowski K(1), Piotrowska A(1), Rojewska E(1), Makuch W(1), Mika J(2).

Author information:
(1)Department of Pain Pharmacology, Institute of Pharmacology Polish Academy of
Sciences, 12 Smetna Str., 31-343, Krakow, Poland.
(2)Department of Pain Pharmacology, Institute of Pharmacology Polish Academy of
Sciences, 12 Smetna Str., 31-343, Krakow, Poland. .

Increasing evidence has indicated that activated glial cells releasing
nociceptive factors, such as interleukins and chemokines, are of key importance
for neuropathic pain. Significant changes in the production of nociceptive
factors are associated with the low effectiveness of opioids in neuropathic pain.
Recently, it has been suggested that CCL2/CCR2 signaling is important for
nociception. Here, we studied the time course changes in the mRNA/protein level
of CD40/Iba-1, CCL2 and CCR2 in the spinal cord/dorsal root ganglia (DRG) in rats
following chronic constriction injury (CCI) of the sciatic nerve. Moreover, we
examined the influence of intrathecal preemptive and repeated (daily for 7 days)
administration of RS504393, CCR2 antagonist, on pain-related behavior and the
associated biochemical changes of some nociceptive factors as well as its
influence on opioid effectiveness. We observed simultaneous upregulation of
Iba-1, CCL2, CCR2 in the spinal cord on 7th day after CCI. Additionally, we
demonstrated that repeated administration of RS504393 not only attenuated
tactile/thermal hypersensitivity but also enhanced the analgesic properties of
morphine and buprenorphine under neuropathy. Our results proof that repeated
administration of RS504393 reduced the mRNA and/or protein levels of
pronociceptive factors, such as IL-1beta, IL-18, IL-6 and inducible nitric oxide
synthase (iNOS), and some of their receptors in the spinal cord and/or DRG.
Furthermore, RS504393 elevated the spinal protein level of antinociceptive
IL-1alpha and IL-18 binding protein. Our data provide new evidence that CCR2 is a
promising target for diminishing neuropathic pain and enhancing the opioid
analgesic effects.