Discovery of a novel COX-2 inhibitor as an orally potent anti-pyretic and anti-inflammatory drug: Design, synthesis, and structure–activity relationship

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

“…On the other hand, it has been reported that COX-2 inhibitors or traditional NSAIDs showed no or agent structure/ character-dependent potential cardiovascular-risk in long-term clinical studies with attention to permanent blockade against COX-2 [94][95][96] , and that COX-2 selective inhibition improved endothelial function in coronary artery disease derived from vascular-inflammation and oxidative-stress in clinical study 97 , and attenuated cardiovascular-failure and liver-damage induced by endotoxin in rat model study 98 , which show importance of safety-index assessment for respective COX-2 inhibitors in longterm use and other clinical potential of COX-2 inhibitors for the treatment of cardiovascular-and liver-diseases as already mentioned in the previous report by Hayashi et al 25 Accordingly, discovery of potent and selective diversechemotypes of COX-2 inhibitors has become increasingly important to meet the above various clinical needs with no or minimal/controllable adverse effects, and to reveal the molecular mechanisms of enzyme inhibition by COX-2 inhibitor in vitro and in vivo. As approaches for elucidation of ligand-COX-2 interaction mechanisms and for (further) drug-design of potent and selective COX-2 inhibitors, the studies of X-ray protein-crystallography and molecular-structure/-docking calculation for COX isozymes with or without ligands have been reported [99][100][101][102][103] .…”

“…25 by Hayashi et al). Significantly, COX-2 is associated with prostaglandin E 2 (PGE 2 ) and prostacyclin (PGI 2 ) production that evokes or sustains systemic or peripheral inflammatory-diseases and/or -symptoms 4,5,25 but it is not involved in the COX-1-mediated GI tract events [15][16][17] . As well, the inhibitory actions of traditional NSAIDs that include aspirin (acetylsalicylic acid) against COX-1 can be crucial problems in clinical pharmacotherapy, such as respiratory-and cutaneous-hypersensitivities and cross-reactivities [26][27][28] .…”

“…COX-2 is absent or exhibits a low level of expression in most tissues, and is highly upregulated in response to inflammatory or tissue-injury stimuli/signals, growth factors, endotoxin, viruses, proinflammatory cytokines, activated T lymphocytes, carcinogens/tumourpromoters and hyperglycemia-induced mitochondrial reactiveoxygen species in the various types of organs, tissues and cells 2,6,7,10,[18][19][20][21][22][23][24] (Ref. 25 by Hayashi et al). Significantly, COX-2 is associated with prostaglandin E 2 (PGE 2 ) and prostacyclin (PGI 2 ) production that evokes or sustains systemic or peripheral inflammatory-diseases and/or -symptoms 4,5,25 but it is not involved in the COX-1-mediated GI tract events [15][16][17] .…”

“…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.…”

Synthesis and Antitumor Evaluation of Novel 5-Bromo Indole-Aryl Keto Hydrazide-Hydrazone Analogues

“…Previously indole-hydrazide-hydrazone derivatives shows antimicrobial [11][12][13][14][15][16][17], antifungal [18], anticonvulsant [19], anti-inflammatory, antiplatelet [20][21][22][23][24] and antituberculosis activities [25][26][27][28]. But these series of indole fused aryl aldehydes analogues shows potent antitumor [29][30][31][32][33] activity on anticancer [34][35][36] human cell lines.…”