title: Design and synthesis of novel cyclooxygenase-1 inhibitors as analgesics: 5-amino-2-ethoxy-N-(substituted-phenyl)benzamides.
abstract: 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.
authors.affiliation: Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Fukai
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zheng
authors.forename: Kazunori
authors.initials: K
authors.lastname: Motoshima
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tai
authors.forename: Futoshi
authors.initials: F
authors.lastname: Yazama
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D001665:Binding Sites; D003198:Computer Simulation; D051545:Cyclooxygenase 1 / Q000737:chemistry* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice
chemical_list: C559678:5-amino-2-ethoxy-N-(2-methoxyphenyl)benzamide; C559679:5-amino-2-ethoxy-N-(3-trifluoromethylphenyl)benzamide; D000700:Analgesics; D001549:Benzamides; D016861:Cyclooxygenase Inhibitors; D051545:Cyclooxygenase 1