Metabolic synthesis of arylacetic acid antiinflammatory drugs from arylhexenoic acids. 2. Indomethacin

• Published in: Journal of medicinal chemistry Vol. 30; no. 11; pp. 2051 - 2058
• Main Authors: Gillard, J. W, Belanger, P
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.11.1987; Amer Chemical Soc
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - pharmacology; Chemistry, Medicinal; Indomethacin - metabolism; Indomethacin - pharmacology; Life Sciences & Biomedicine; Pharmaceutical Preparations - chemical synthesis; Pharmacology & Pharmacy; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Rats; Science & Technology; Species Specificity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00394a020

Arylacetic acid antiinflammatory drugs can be metabolically produced by .beta.-oxidation of a 6-arylhex-5-enoic acid side chain. Such a mechanism provides an in vivo [mice and rats] sustained release of the active principle indomethacin from 6-[N-(p-chlorobenzoyl)-2-methylindol-3-yl]hex-5-enoic acid (7). Similarly, biphenylacetic acid was produced from both 6-(4''-biphenylyl)hex-5-enoic acid and its lower even homologue, 4-(4''-biphenylyl)but-3-enoic acid. The indole derivative produced sustained analgesia in a yeast-induced hyperalgesia model over a 12-h period. Indomethacin plasma levels of 2 .mu.g/mL were observed for up to 24 h. Such levels were less than those achieved for the analogous case in which biphenylacetic acid was produced from biphenylylhex-5-enoic acid, suggesting metabolic discrimination between hex-5-enoic substrates. When indomethacin was dosed in equipotent analgesic levels, the level of circulating drug was considerably higher than that seen for metabolically derived drug. Hence 6-hex-5-enoic acid derivatives of indomethacin are metabolized to indomethacin in vivo to give sustained analgesia at low apparent circulating plasma levels of free drug. The possibility of tissue compartmentalization enhancing biological efficacy is suggested by these observations.