Novel Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Anti-Inflammatory and Analgesic Agents. Synthesis and in Vitro and in Vivo Biological Evaluation

Abstract

A new generation of selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) was developed to circumvent the major side effects of cyclooxygenase-1 (COX-1) and COX-2 inhibitors (stomach ulceration and nephrotoxicity). As a consequence, coxibs are extremely valuable in treating acute and chronic inflammatory conditions. However, the use of coxibs, such as rofecoxib (Vioxx), was discontinued because of the high risk of cardiovascular adverse events. More recent clinical findings highlighted how the cardiovascular toxicity of coxibs could be mitigated by an appropriate COX-1 versus COX-2 selectivity. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, selective for COX-2. Here, we describe the synthesis of new 1,5-diarylpyrroles along with their inhibitory effects in vitro, ex vivo, and in vivo toward COX isoenzymes and their analgesic activity. Isopropyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1H-pyrrole-3-acetate (10a), a representative member of the series, was selected for pharmacokinetic and metabolic studies.

Synthesis, biological evaluation and docking analysis of a new series of methylsulfonyl and sulfamoyl acetamides and ethyl acetates as potent COX-2 inhibitors

“…Briefly, 4-sulfonmethylphenyl acetic acids 13a,b were obtained following the procedure previously described. 10 The coupling stage which led to acetamides 1-4 was afforded in the presence of EDCI and DMAP and the appropriate amine.…”

“…Briefly, pyrroles 14a,b have been prepared as previously described. 10 Generation of the carbanion with butyllithium on aryl methyl sulfones 14a,b, followed by addition of iodomethyltrimethylsilane gave the trimethylsilylethyl sulfone intermediates 15a,b. Desilylation with tetrabutylammonium fluoride to the sulfinic acid salts followed by treatment with hydroxylamine-O-sulfonic acid in the microwave apparatus, gave the desired arylsulfonamides 16a,b.…”

“…We have previously reported several studies on the design, synthesis and activity of pyrrole-based COX-2 inhibitors. [6][7][8][9][10][11][12] http://dx.doi.org/10.1016/j.bmc.2014.12.041 0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.…”

“…However, their in vivo profile, was somehow lower than expected, indicating that the chemical and enzymatic liability of these esters play a crucial role in the pharmacokinetic fate of such a class of molecules. 10 Therefore, we present herein our efforts on developing more stable compounds by replacing the ester moiety with an amide one. At first, we have prepared propyl and isopropyl acetic amides 1-4 ( Fig.…”

Synthesis and evaluation of anti-inflammatory, analgesic, ulcerogenicity and nitric oxide-releasing studies of novel ibuprofen analogs as nonulcerogenic derivatives

“…These drugs reduce pain and edema by suppressing the formation of prostaglandins, by inhibiting the activity of the enzyme Cyclooxygenase (COX-1 and COX-2). Selective COX-2 inhibitors elicit less or no GI damage and bleeding compared with conventional NSAIDs, although the magnitude of this reduction continues to be debated in the literature (Szabó et al, 2008;Biava et al, 2010). As widely reported in the laypress, the selective COX-2 inhibitors also cause significant adverse effects in the renal and cardiovascular systems, possibly more serious than those caused by conventional NSAIDs.…”