We previously found that N-(4-aminophenyl)-4-trifluoromethylbenzamide (TFAP), a COX-1 inhibitor, exhibits an analgesic effect without causing gastric damage. Unfortunately, TFAP causes reddish purple coloration of urine, and its analgesic effect is less potent than that of indomethacin. Herein we describe our study focusing on the development of 4- and 5-amino-2-alkoxy-N-phenylbenzamide scaffolds, designed on the basis of the structures of TFAP and parsalmide, another known COX-1 inhibitory analgesic agent. 5-Amino-2-ethoxy-N-(2- or 3-substituted phenyl)benzamide derivatives exhibited analgesic activity in a murine acetic acid induced writhing test. Among these compounds, 5-amino-2-ethoxy-N-(2-methoxyphenyl)benzamide (9 v) possesses potent COX-1 inhibitory and analgesic activities, similar to those of indomethacin. In addition, 5-amino-2-ethoxy-N-(3-trifluoromethylphenyl)benzamide (9 g) showed a more potent analgesic effect than indomethacin or 9 v without causing apparent gastric damage or coloration of urine, although its COX-1 inhibitory activity was weaker than that of indomethacin or 9 v. Thus, 9 g and 9 v appear to be promising candidates for analgesic agents and are attractive lead compounds for further development of COX-1 inhibitors.
Non-steroidal anti-in‰ammatory drugs (NSAIDs) are widely used to relieve physical and mental pain, and to improve patients' quality of life. However, stomach irritation is a major side eŠect. Most NSAIDs inhibit cyclooxygenases (COXs), and inhibition of COX-1 on the stomach mucous membrane is thought to be responsible for the gastric disturbance. Consequently, development eŠorts have focused on COX-2-selective inhibitors, while COX-1-selective inhibitors have been rather neglected. Subsequently, however, it was shown that inhibition of either COX-1 or COX-2 alone does not induce gastric damage. Therefore, we have developed the COX-1-selective inhibitor N-(4-aminophenyl)-4-tri‰uoromethylbenzamide (TFAP), which shows analgesic activity without causing gastric damage. However, metabolism of TFAP generates a colored metabolite, resulting in red-purple coloration of urine after administration. In addition, the analgesic activity of TFAP is weaker than that of indomethacin. Thus, we designed a series of new COX-1-selective inhibitors, the 5-amino-2-ethoxy-N-(substituted)benzamide (ABEX) series, in order to avoid formation of the colored metabolite by modifying the diaminopyridine skeleton. As a result of structural modiˆcation and in vitro and in vivo testing of compounds in the ABEX series, we found a novel COX-1-selective inhibitor, 5-amino-2-ethoxy-N-(3-tri‰uoromethylphenyl)benzamide (ABEX-3TF), which shows better analgesic activity than indomethacin, and does not cause coloration of urine.
This is the first report describing subacute volar dislocation of the distal radioulnar joint treated by open reduction and stabilization of the distal radioulnar joint by means of a suture anchor. Acute volar dislocation of the distal radioulnar joint successfully treated by closed or open reduction has previously been reported. In our case, surgery was performed five weeks after the initial injury. Good stabilization was obtained by reattaching the triangular fibrocartilage complex to the ulnar fovea with a suture anchor. It is important not to misdiagnose distal radioulnar joint dislocation, and the suture anchor technique is an effective treatment option.
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