Discovery of two new co-drugs of celecoxib and gabapentinoids for treating chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) represents a common dose-limiting adverse effect of chemotherapeutic drugs, affecting 25-90% of cancer patients. However, currently available medications often show limited efficacy for CIPN, which necessitates the development of novel analgesics. An emerging perspective is that neuroinflammation represents one of the possible pathogeneses underlying CIPN. In our studies, isobolographic analysis revealed that co-administration of celecoxib with pregabalin or gabapentin produced antinociceptive effects for CIPN. Based on multimodal analgesia, two new co-drugs CEL-PRE and CEL-GBP were synthesized from celecoxib with pregabalin/gabapentin to achieve synergistic antinociceptive effects for CIPN. Both CEL-PRE and CEL-GBP showed more than 200 times higher water solubility than celecoxib. In vitro liver microsome assays showed that these co-drugs can be metabolized into two parent drugs within 30 min. CEL-PRE and CEL-GBP exhibited significant efficacy in paclitaxel-induced neuropathic pain models with ED 50 values of 4.27 mg/kg and 6.55 mg/kg, respectively. At equimolar doses, CEL-PRE and CEL-GBP demonstrated superior antinociceptive effects than single drugs for paclitaxel-induced neuropathy. Both of the two co-drugs can alleviate inflammation by inhibiting inflammatory mediators (IL-6, IL-1β, TNF-α, COX-2, and PGE 2 ) and suppress the expression of neuronal c-Fos, which were significantly elevated in CIPN. Additionally, CEL-PRE and CEL-GBP do not affect motor coordination in rotarod tests. Therefore, novel co-drugs CEL-PRE and CEL-GBP are promising candidates for treating CIPN.