Novel acid-type cyclooxygenase-2 inhibitors: Design, synthesis, and structure–activity relationship for anti-inflammatory drug

Design, synthesis and structure–activity relationship studies of novel and diverse cyclooxygenase-2 inhibitors as anti-inflammatory drugs

“…Specific pathogen free and virus antibody free (SPF/VAF) male SpragueDawley (SD) rats [Crj:CD(SD), 5 weeks old, 110-130 g, Charles River Laboratories, Japan Inc., Hino, Tokyo, Japan] that were fasted overnight were injected intraplantarly with 0.1 mL of a 1% (w/v) -carrageenan (Picnin-A) suspension in saline into the right hind paw as previously reported 25,104,[115][116][117] . Either the vehicle [5% (v/v) Tween 80 in distilled water] or a test compound was dosed orally in a volume of 1 mL/100 g body weight at 1 h before carrageenan injection.…”

“…Platelets were pre-incubated in the absence or presence of 10 mL of test compound dissolved in DMSO at final concentrations varying 0.01-10 mM (final concentration, less than 0.1%) for 20 min before stimulation with 10 mL of A23187 (final concentration, 10 mM). After further 15 min incubation at 37 C with A23187, the reaction was stopped by the addition of EDTA (final concentration, 7.7 mM), and the reaction medium was quantitated for TXB 2 by a radioimmunoassay (RIA) kit (Amersham, Little Chalfont, Buckinghamshire, UK) according to the manufacturer's procedure 25,104,113 .…”

“…The human cell-based COX-2 assay was carried out as previously described 25,104,114 . Confluent HUVECs (2 Â 10 4 cells/well) in a 96-well plate were washed with 100 mL of RPMI-1640 containing 2% foetal calf serum (FCS), and incubated with 300 U/mL of recombinant human IL-1b for 24 h at 37 C for induction of COX-2.…”

“…Besides, it has been described already, design, synthesis and in vitro and in vivo structure-activity relationship (SAR) studies for novel [2-{[(4-substituted or 4,5-disubstituted)-pyridin-2-yl]carbonyl}-(5-or 6-substituted or 5,6-disubstituted)-1H-indol-3-yl]acetic acid analogues were investigated by Hayashi et al 25,104 , which resulted in the discoveries of novel acid-types of COX-2 inhibitors as a new-class of orally potent anti-pyretic and/or anti-inflammatory drugs in vivo; also, it has been shown in the studies that the mechanisms of orally potent anti-pyretic effect and anti-oedematous effect in the in vivo models for the analogues were due to their respective highly potent and selective, intrinsic COX-2 inhibitions. In this study, design, synthesis and SAR of diverse novel {2-[(2-, 3-or 4-substituted, or 2,4-or 3,4-disubstituted)-benzoyl, (bicyclic heterocycloalkanophenyl) carbonyl or cycloalkanecarbonyl]-(5-or 6-substituted)-1H-indol-3-yl}acetic acid analogues were investigated to seek and identify various chemotypes of orally potent and selective COX-2 inhibitors as potential agents for the treatment of inflammatory diseases.…”

“…0.520 mmol); that was synthesised by us at Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc. (Aichi, Japan) according to the reported procedure by Hayashi et al 104 Step 2. [2-(4-Chlorobenzoyl)-6-fluoro-1H-indol-3-yl]acetic acid (44a).…”