Properties and Synthesis of 2-{2-Fluoro (or Bromo)-4-[(2-oxocyclopentyl)methyl]phenyl}propanoic Acid: Nonsteroidal Anti-inflammatory Drugs with Low Membrane Permeabilizing and Gastric Lesion-Producing Activities

Abstract

We previously proposed that membrane permeabilization activity of NSAIDs is involved in NSAID-induced gastric lesions. We here synthesized derivatives of loxoprofen that have lower membrane permeabilization activity than other NSAIDs. Compared to loxoprofen, the derivatives 10a and 10b have lower membrane permeabilization activity and their oral administration produced fewer gastric lesions but showed an equivalent anti-inflammatory effect. These results suggest that 10a and 10b are likely to be therapeutically beneficial as safer NSAIDs.

Synthesis and biological evaluation of loxoprofen derivatives

“…a Data from our previous report. 25 in vitro observation that the inhibitory effect of 1 on COX-2 was indistinguishable from that of 31 (Table 2). The inhibitory activity of 31 on COX-2 was much higher than that of 23 (Table 2), indicating the importance of the modification position of the phenyl ring (3-or 2-position) for determining the inhibitory effect on COX-2.…”

“…Synthesis of loxoprofen derivatives with modification at the 2-position of the phenyl ring by a para-substituted aryl group (24)(25)(26)(27)(28)(29)(30)(31)(32)(33) rings. We previously reported that two of the compounds, 2-fluoroloxoprofen 4a and 2-bromoloxoprofen 4b (Fig.…”

“…1), have lower membrane permeabilization activity than 1. 25 In this study, we examined the membrane permeabilization activities and inhibitory effects on COX-1 and COX-2 of other derivatives to find other valuable compounds, such as those with COX-2 specificity.…”

“…A key intermediate 4b was prepared, as described previously. 25 The methyl ester of 4b was prepared by treatment with methanol in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and N,N-dimethyl-4-aminopyridine (DMAP). After the cross-coupling reaction between the compound 4b and a variety of boronic acids, the ester group was converted to a carboxylic acid group by alkaline hydrolysis, followed by acidification.…”

“…Nevertheless, these compounds had equivalent antiinflammatory effects compared to loxoprofen. 25 In the present study, we synthesized a series of loxoprofen derivatives and examined their membrane permeabilization activities and inhibitory effects on COX-1 and COX-2. Among these derivatives, 2-{4 0 -hydroxy-5-[(2-oxocyclopentyl)methyl]biphenyl-2-yl}propanoate (31, Scheme 3) has a specificity for COX-2 and its oral administration produced fewer gastric lesions but showed an equivalent antiinflammatory effect, compared to loxoprofen.…”