Chem. Pharm. Bull. 53(9) 1103—1110 (2005)

Glycyrrhiza species (G. uralensis, G. glabra, and G. inflata) has been reported to possess various pharmacological activities such as anti-inflammation, inhibition of prostaglandin E2 (PGE2) production in rat macrophages, 2) antiallergic, antiviral action, and interferon-g-induction. In Japan, a glycyrrhizin preparation, Stronger-Neo Minophagen C (SNMC), has been used extensively for more than 30 years to treat chronic hepatitis. Glycyrrhetinic acid (GA), the aglycon of GL, is also known to have wide pharmacological effects such as anti-inflammation, antitumor, antihepatotoxic activity, and inhibition of the growth of mouse melanoma. In 1989, it was reported that GA strongly inhibits renal 11b-hydroxysteroid dehydrogenase (11b-HSD) in rat, which has been regarded as a cause of pseudoaldosteronism occasionally induced by the administration of a GL preparation or Carbenoxolone. We have synthesized various GA derivatives, such as deoxo-glycyrrhetol (1), olean-11,13(18)-dien-3b ,30-diol (2), and their succinate or hemi-phthalate forms (Fig. 1), in order to enhance the anti-inflammatory activity and suppress the pseudoaldosteronism due to the inhibition of mineralcorticoid metabolism. During the course of this work, 3 was reported to show various anti-inflammatory activities such as the inhibition of increasing vascular permeability, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema, arachidonic acid-induced or capsaicin-induced mouse ear edema, and carrageenin-induced rat paw edema. It was suggested that one of the mechanisms by which 3 induces anti-inflammatory effects is the inhibition of cyclooxygenase or lipoxygenase activities at the inflammatory site. Interestingly, it was found that 3 exhibited antiacetic acid-induced writhing activity and an antiulcer activity, in addition to the anti-inflammation. In addition, we have reported that 3 did not inhibit the activity of 11b-HSD2, which causes an adverse effect of GA. These facts suggest that 3 is promising as a lead compound for a new type of anti-inflammatory agent, showing anti-inflammatory action as well as anti-ulcer action, different from conventional nonsteroidal anti-inflammatory drugs (NSAIDs), which are mostly ulcerogenic. Recently, confirmed that normal human dermal fibroblasts (NHDF) produce PGE2 in response to IL-1b . In fact, NHDF have been used to assess the effect of compounds such as Tranilast and Azelastine on PGE2 production. 24,25) However, it is unclear whether 3 and its derivatives have an effect on COX-2 dependent PGE2 production. In this paper, we synthesized various new compounds derived from 3 and examined the effect of these compounds on IL-1b-induced PGE2 production in NHDF. September 2005 Chem. Pharm. Bull. 53(9) 1103—1110 (2005) 1103