CXCR4 modulator that does not target prostaglandin pathway (does not inhibit COX pathway) for treatment of inflammation.
- New class of anti-inflammatory drugs targeting CXCR4 instead of COX pathway.
- May serve as safe anti-inflammatory drugs.
CXC chemokine receptor 4 (CXCR4) and stromal cell-derived factor 1 (SDF-1) are a chemokine receptor and chemokine pair that play a critical role in cancer metastasis and inflammation. The COX pathway has long been used as the major target for anti-inflammatory drugs. Both traditional non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors exhibit their anti-inflammatory activity by inhibiting COX-2. The prolonged use of traditional anti-inflammatory drugs is associated with potential serious side effects such as kidney failure, ulcers and prolonged bleeding after an injury or surgery. Two NSAIDs were withdrawn from the market due to an increased risk of cardiovascular complications. Accumulating evidence suggests the involvement of CXCR4/SDF-1 interaction in various inflammatory diseases, including rheumatoid arthritis, autoimmune diseases, ischemic injuries, inflammatory bowel disease, and pneumonia.
CXCR4 inhibitors are promising agents for the treatment of inflammation. A series of novel tertiary amine derivatives uniquely modulating CXCR4 were designed, synthesized, and evaluated. The central benzene ring linker and side chains were modified and optimized to study the structure–activity relationships. The compounds have been selected via in vitro testing to determine their CXCR4 modulating activities and potency. These compounds have the potential for complementary therapeutic strategy in inflammatory diseases, viral infections, and cancer metastasis.
Selected compounds were tested in animal models of inflammation.