Design and Development of COX-II Inhibitors: Current Scenario and Future Perspective

Abstract

Innate inflammation beyond a threshold is a significant problem involved in cardiovascular diseases, cancer, and many other chronic conditions. Cyclooxygenase (COX) enzymes are key inflammatory markers as they catalyze prostaglandins production and are crucial for inflammation processes. While COX-I is constitutively expressed and is generally involved in "housekeeping" roles, the expression of the COX-II isoform is induced by the stimulation of different inflammatory cytokines and also promotes the further generation of pro-inflammatory cytokines and chemokines, which affect the prognosis of various diseases. Hence, COX-II is considered an important therapeutic target for drug development against inflammation-related illnesses. Several selective COX-II inhibitors with safe gastric safety profiles features that do not cause gastrointestinal complications associated with classic antiinflammatory drugs have been developed. Nevertheless, there is mounting evidence of cardiovascular side effects from COX-II inhibitors that resulted in the withdrawal of market-approved anti-COX-II drugs. This necessitates the development of COX-II inhibitors that not only exhibit inhibit potency but also are free of side effects. Probing the scaffold diversity of known inhibitors is vital to achieving this goal. A systematic review and discussion on the scaffold diversity of COX inhibitors are still limited. To address this gap, herein we present an overview of chemical structures and inhibitory activity of different scaffolds of known COX-II inhibitors. The insights from this article could be helpful in seeding the development of next-generation COX-II inhibitors.

COX inhibitory profiles of a series of thiadiazole-benzothiazole hybrids

“…COX-1 and 2, two major isoforms of COX, are membrane-bound enzymes located in the endoplasmic reticulum and the nuclear envelope. COX-1 is the housekeeper isoform implicated in the maintenance of homeostasis, the protection of the gastric mucosa, the regulation of platelet aggregation, and renal perfusion [3]. On the other hand, COX-2 is the inducible isoform of COX that is associated with the disease-related inflammatory reactions [3,4].…”

Design of Balanced Cyclooxygenase Inhibitors Based on Natural Anti‐inflammatory Ascidian Metabolites and Celecoxib

“…Specifically, both COX-1 and COX-2 isoforms have been identified are critical targets for NSAID action. [5][6][7][8][9] COX-1 is an intrinsic isoenzyme found in most cells, and prostaglandins catalyzed by COX-1 exhibit gastroprotective effects. [10] In contrast, COX-2 belongs to an inducible enzyme that is highly expressed in inflammatory cells and triggered by specific cellular actions, PGs converted by COX-2 cause a range of inflammatory symptoms.…”

Modifications of 4‐Amino‐substituted 5‐Phenyl‐3‐(trifluoromethyl)pyrazoles for the Development of New Analgesics

“…The functionalization of the pyrazole scaffold is a modern trend for the design of not only compounds with various types of biological activity but also new drugs. [1][2][3][4][5][6][7][8][9][10][11][12] Fluorine-containing pyrazoles have special advantages in medicinal chemistry [13][14][15] due to the unique properties of fluorine atoms; their presence in an organic compound leads to an increase in their lipophilicity and metabolic stability, as well as a change in the nature of intermolecular interactions, etc. [16][17][18][19] Based on the fluorine-containing pyrazole core, such drugs as celecoxib (an anti-inflammatory drug, a selective COX-2 inhibitor), [20] acrizanib (a VEGFR-2 inhibitor), [21] and lenacapavir (an anti-HIV drug) [22] have been developed and which are actively used in medical practice.…”

“…The functionalization of the pyrazole scaffold is a modern trend for the design of not only compounds with various types of biological activity but also new drugs [1–12] . Fluorine‐containing pyrazoles have special advantages in medicinal chemistry [13–15] due to the unique properties of fluorine atoms; their presence in an organic compound leads to an increase in their lipophilicity and metabolic stability, as well as a change in the nature of intermolecular interactions, etc [16–19] .…”