Inflammatory and pain are major areas for drug discovery. Current analgesic drugs often cause a number of side-effects. In the present study, we modified carboxylic acid group of ibuprofen, one of non-steroidal anti-inflammatory drugs, based on the common structure of transient receptor potential vanilloid type 1 antagonists which are considered as new candidates for analgesic drugs, and synthesized several derivatives of ibuprofen. Comprehensive evaluations of the pharmacological properties of these compounds were investigated. Compound 17 showed weak cyclooxygenase inhibition and exhibited strong transient receptor potential vanilloid type 1 antagonistic activity. It was found to be capable of blocking noxious thermal nociception and capsaicin-induced nociception in mice. Besides, 17 showed less ulcerogenic action than ibuprofen did and had no hyperthermia side-effect compared with common transient receptor potential vanilloid type 1 antagonists. Therefore, it suggested that 17 could be used as a safe alternative analgesic candidate for pain treatment.
A series of piperazine carboxamide, propanamide, and pyrrolidine carboxamide derivatives of ibuprofen were designed by modifying carboxylic acid group of ibuprofen based on the common structure of transient receptor potential vanilloid type 1 (TRPV1) antagonists and synthesized. They were evaluated for cyclooxygenase inhibition, TRPV1 antagonistic, anti-inflammatory, analgesic, ulcerogenic action, and the effect on body temperature. Compound 17 emerged as a safe alternative analgesic candidate for pain treatment.