Evaluation of 2 celecoxib derivatives: analgesic effect and selectivity to cyclooxygenase-2/11

Abstract

Aim: To evaluate the analgesic effects of 2 celecoxib derivatives and their inhibitory effects on cyclooxygenase (COX). Methods: Four antinociceptive assays were used: the acetic acid-induced writhing test, hot plate test, hot tail-flick test and formalin test. Three doses were used in the analgesic assays and ED 50 values were calculated. For the selectivity assay, macrophages were incubated with test compounds at various concentrations and then stimulated with calcimycin or lipopolysaccharide (LPS). The amounts of 6-keto-prostaglandin F 1α (6-keto-PGF 1α ) and prostaglandin E 2 (PGE 2 ) in the supernatant were examined by radioimmunoassay (RIA). The selectivity of the test compounds was expressed as the IC 50,COX-1 / IC 50,COX-2 value. Results: Celecoxib and its 2 derivatives had a significant analgesic effect. The ED 50 values of celecoxib, PC-406 and PC-407 were 94.2, 67.9, and 63.3 mg/kg, respectively, for the acetic acid-induced writhing test; 104.7, 89.1, and 30.0 mg/kg, respectively, for the hot tail-flick response test; 60.7, 56.7, and 86.2 mg/kg, respectively, for the hot plate response test; 67.1, 55.8, and 68.8 mg/kg, respectively, for the formalin-induced response. That is, the ED 50 of PC-406 was the lowest for the formalin and hot plate tests, which focus on changes above the spinal cord level; however, the ED 50 of PC-407 was lowest for the tail-flick and writhing tests, which focus on changes at the spinal cord level. Celecoxib and PC-407 inhibited COX-1 with IC 50 values of 39.8 and 27.5 nmol/L, respectively. PC-406 inhibited COX-1 with an IC 50 value of more than 1000 nmol/L. The IC 50 values for the effect of celecoxib, PC-406 and PC-407 on COX-2 were 4.8, 8.9, and 1.9 nmol/L respectively. The IC 50,COX-1 /IC 50,COX-2 ratios for celecoxib and PC-407 were 8.3 and 14.4, respectively. For PC-406, the ratio was greater than 112.2. Conclusion: Derivatives of celecoxib via substitution with an isopropyl or naphthyl group at the 5 position in the pyrazole ring still have analgesic effects and the ability to selectively inhibit COX-2. Substitution with a naphthyl group may have more effect on the peripheral pain pathway, whereas substitution with an isopropyl group may have more effect on the central pain pathway. This phenomenon occurs partly because substitution with an isopropyl group is more beneficial for COX-2 selectivity than is substitution with a naphthyl group.

Involvement of Spinal CB1 Cannabinoid Receptors on the Antinociceptive Effect of Celecoxib in Rat Formalin Test

“…The study indicated that IT celecoxib had antinociceptive activity in late phase of formalin test in a dose-dependent manner. These data are in agreement with other studies in which IT celecoxib administration could inhibit nociception in both phases of formalin test (26)(27)(28)(29)(30).…”

Enhanced water-soluble derivative of PC407 as a novel potential COX-2 inhibitor injectable formulation

“…On the contrary, reference drug PC407 exhibited 100% inhibition of COX-2 isoform, without any inhibition of COX-1 isoform at 0.1 lM concentration, which was consistent with the known facts. 4,11 As expected, prodrug 3b showed relatively less potency in COX-2 inhibition in vitro than PC407 due to the block of sulfonamide, which is the main pharmacophore group in PC407. 11 In vivo pharmacological evaluation of the water soluble prodrug 3b was carried out to assess their potential analgesic activity in the acetic acid-induced writhing assay.…”

“…4,11 As expected, prodrug 3b showed relatively less potency in COX-2 inhibition in vitro than PC407 due to the block of sulfonamide, which is the main pharmacophore group in PC407. 11 In vivo pharmacological evaluation of the water soluble prodrug 3b was carried out to assess their potential analgesic activity in the acetic acid-induced writhing assay. [20][21][22] The writhing test is a nociceptive model characterized by repeated contractions of the abdominal muscles.…”

“…The parent drug PC407 required for the synthesis of prodrug, was prepared according to the procedures reported by Penning group 4 or our group. [11][12][13][14] Briefly, reacting 1-(naphthalen-2-yl)ethanone 4 with ethyl trifluoroacetate in the presence of NaOMe provided the expected 1,3-dicarbonyl adduct 5, which was carried out by the condensation with 4-hydrazinobenzenesulfonsmide hydrochloride in anhydrous EtOH under refluxing condition to give the desired product. The pure PC407 (3a) was readily isolated by flash silica chromatography in 44% yield.…”

“…1) is a promising celecoxib analog developed by our group with potent pharmacological activities in the treatment of pain, inflammation and antiproliferation based on the role of COX-2 in the etiopathology of those diseases. [11][12][13][14][15] Recent surveys have shown that many patients underwent surgery experience with severe or moderately severe operative and postoperative pain which were poorly managed in clinical trials. COX-2 inhibitors have been proved to reduce acute to moderate pain by targeting the COX-2 enzyme expressed at sites of injury including surgical incisions recently.…”