Browse
Submit Data
Databases
API
Help

Dataset Information

8 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Selective COX-2 Inhibitors: Road from Success to Controversy and the Quest for Repurposing

ABSTRACT: The introduction of selective COX-2 inhibitors (so-called ‘coxibs’) has demonstrated tremendous commercial success due to their claimed lower potential of serious gastrointestinal adverse effects than traditional NSAIDs. However, following the repeated questioning on safety concerns, the coxibs ‘controversial me-too’ saga increased substantially, inferring to the risk of cardiovascular complications, subsequently leading to the voluntary withdrawal of coxibs (e.g., rofecoxib and valdecoxib) from the market. For instance, the makers (Pfizer and Merck) had to allegedly settle individual claims of cardiovascular hazards from celecoxib and valdecoxib. Undoubtedly, the lessons drawn from this saga revealed the flaws in drug surveillance and regulation, and taught science to pursue a more integrated translational approach for data acquisition and interpretation, prompting science-based strategies of risk avoidance in order to sustain the value of such drugs, rather than their withdrawal. Looking forward, coxibs are now being studied for repurposing, given their possible implications in the management of a myriad of diseases, including cancer, epilepsy, psychiatric disorders, obesity, Alzheimer’s disease, and so on. This article briefly summarizes the development of COX-2 inhibitors to their market impression, followed by the controversy related to their toxicity. In addition, the events recollected in hindsight (the past lessons), the optimistic step towards drug repurposing (the present), and the potential for forthcoming success (the future) are also discussed.

SUBMITTER: El-Malah A

PROVIDER: S-EPMC9318302 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Ortho-carbaborane derivatives of indomethacin as cyclooxygenase (COX)-2 selective inhibitors.

Project description:A series of novel indomethacin analogues with carbaboranes as three-dimensional substitutes for the chlorophenyl ring have been prepared. Their cyclooxygenase (COX) inhibition and enzyme selectivity has been tested and compared to the corresponding adamantyl analogues. Surprisingly, only the ortho-carbaborane derivatives were active compounds. Preliminary biological studies gave an interesting insight into the validity of employing carbaboranes as pharmacophores.

| S-EPMC3408963 | biostudies-literature

Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors.

Project description:The usefulness of non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by their gastrointestinal side effects. Non-selective cyclooxygenases inhibitors interfere with both COX-1 and COX-2 isozymes. Since COX-1 mediates cytoprotection of gastric mucosa, its inhibition leads to the undesirable side effects. On the other hand, COX-2 is undetectable in normal tissues and selectively induced by inflammatory stimuli. Therefore, it is strongly believed that the therapeutic benefits derive from inhibition of COX-2 only. The presence of a strong connection between reported COX-2 inhibitors and cardiac toxicity encourages medicinal chemists to explore new scaffolds. In the present study, we introduced imidazopyrazolopyridines as new potent and selective COX-2 inhibitors that lack the standard pharmacophoric binding features to hERG. Starting from our lead compound 5a, structure-based drug-design was conducted and more potent analogues were obtained with high COX-2 selectivity and almost full edema protection, in carrageenan-induced edema assay, in case of compound 5e. Increased bulkiness around imidazopyrazolopyridines by adding a substituted phenyl ring(s) afforded less active compounds.

| S-EPMC6332013 | biostudies-literature

Chondroprotective Actions of Selective COX-2 Inhibitors In Vivo: A Systematic Review.

Project description:Knee osteoarthritis (OA) is a condition mainly characterized by cartilage degradation. Currently, no effective treatment exists to slow down the progression of OA-related cartilage damage. Selective COX-2 inhibitors may, next to their pain killing properties, act chondroprotective in vivo. To determine whether the route of administration is important for the efficacy of the chondroprotective properties of selective COX-2 inhibitors, a systematic review was performed according to the PRISMA guidelines. Studies investigating OA-related cartilage damage of selective COX-2 inhibitors in vivo were included. Nine of the fourteen preclinical studies demonstrated chondroprotective effects of selective COX-2 inhibitors using systemic administration. Five clinical studies were included and, although in general non-randomized, failed to demonstrate chondroprotective actions of oral selective COX-2 inhibitors. All of the four preclinical studies using bolus intra-articular injections demonstrated chondroprotective actions, while one of the three preclinical studies using a slow release system demonstrated chondroprotective actions. Despite the limited evidence in clinical studies that have used the oral administration route, there seems to be a preclinical basis for considering selective COX-2 inhibitors as disease modifying osteoarthritis drugs when used intra-articularly. Intra-articularly injected selective COX-2 inhibitors may hold the potential to provide chondroprotective effects in vivo in clinical studies.

| S-EPMC7555215 | biostudies-literature

(R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2.

Project description:Cyclooxygenase-2 (COX-2) catalyzes the oxygenation of arachidonic acid and the endocannabinoids 2-arachidonoylglycerol and arachidonoylethanolamide. Evaluation of a series of COX-2 inhibitors revealed that many weak competitive inhibitors of arachidonic acid oxygenation are potent inhibitors of endocannabinoid oxygenation. (R) enantiomers of ibuprofen, naproxen and flurbiprofen, which are considered to be inactive as COX-2 inhibitors, are potent 'substrate-selective inhibitors' of endocannabinoid oxygenation. Crystal structures of the COX-2–(R)-naproxen and COX-2–(R)-flurbiprofen complexes verified this unexpected binding and defined the orientation of the (R) enantiomers relative to (S) enantiomers. (R)-Profens selectively inhibited endocannabinoid oxygenation by lipopolysaccharide-stimulated dorsal root ganglion (DRG) cells. Substrate-selective inhibition provides new tools for investigating the role of COX-2 in endocannabinoid oxygenation and a possible explanation for the ability of (R)-profens to maintain endocannabinoid tone in models of neuropathic pain.

| S-EPMC3298755 | biostudies-literature

Effects of a non-selective COX inhibitor and selective COX-2 inhibitors on contractility of human and porcine ureters in vitro and in vivo.

Project description:BACKGROUND AND PURPOSE: Anti-inflammatory drugs are used in the treatment of acute renal colic. The aim of this study was to investigate the effects of selective COX-2 inhibitors and the non-selective COX inhibitor diclofenac on contractility of human and porcine ureters in vitro and in vivo, respectively. COX-1 and COX-2 receptors were identified in human ureter and kidney. EXPERIMENTAL APPROACH: Human ureter samples were used alongside an in vivo pig model with or without partial ureteral obstruction. COX-1 and COX-2 receptors were located in human ureters by immunohistochemistry. KEY RESULTS: Diclofenac and valdecoxib significantly decreased the amplitude of electrically-stimulated contractions in human ureters in vitro, the maximal effect (Vmax) being 120 and 14%, respectively. Valdecoxib was more potent in proximal specimens of human ureter (EC50=7.3 x 10(-11) M) than in distal specimens (EC50=7.4 x 10(-10) M), and the Vmax was more marked in distal specimens (22.5%) than in proximal specimens (8.0%) in vitro. In the in vivo pig model, parecoxib, when compared to the effect of its solvent, significantly decreased the maximal amplitude of contractions (Amax) in non-obstructed ureters but not in obstructed ureters. Diclofenac had no effect on spontaneous contractions of porcine ureter in vivo. COX-1 and COX-2 receptors were found to be expressed in proximal and distal human ureter and in tubulus epithelia of the kidney. CONCLUSIONS AND IMPLICATIONS: Selective COX-2 inhibitors decrease the contractility of non-obstructed, but not obstructed, ureters of the pig in vivo, but have a minimal effect on electrically-induced contractions of human ureters in vitro.

| S-EPMC2483393 | biostudies-other

HIV PrEP Trials: The Road to Success.

Project description:The global HIV epidemic cannot be controlled by current treatment or prevention strategies. Pre-exposure prophylaxis (PrEP) using antiretrovirals is a promising approach to curbing the spread of HIV transmission. Recently, four clinical trials demonstrated favorable results when antiretroviral PrEP was administered topically or orally. However, two additional trials were unable to demonstrate a benefit, indicating that further study is required to define the populations and conditions under which PrEP will be effective. Adherence is highly correlated with protection, yet the exact level of adherence required is unknown. Future studies may require increased drug exposure testing and more objective methods to monitor adherence in real-time. Although the development of drug resistance in the PrEP trials has been low, it remains a concern, as therapeutic options could be compromised for those who seroconvert while on PrEP.

| S-EPMC3882078 | biostudies-literature

Repurposing drugs in oncology (ReDO)-selective PDE5 inhibitors as anti-cancer agents.

Project description:Selective phosphodiesterase 5 inhibitors, including sildenafil, tadalafil and vardenafil, are widely-used in the treatment of erectile dysfunction and pulmonary arterial hypertension. They are also well-known as examples of successful drug repurposing in that they were initially developed for angina and only later developed for erectile dysfunction. However, these drugs may also be effective cancer treatments. A range of evidentiary sources are assessed in this paper and the case made that there is pre-clinical and clinical evidence that these drugs may offer clinical benefit in a range of cancers. In particular, evidence is presented that these drugs have potent immunomodulatory activity that warrants clinical study in combination with check-point inhibition.

| S-EPMC5931815 | biostudies-literature

The Quest for Secondary Pharmaceuticals: Drug Repurposing/Chiral-Switches Combination Strategy.

Project description:Drug repurposing toward new medical uses and chiral switches are elements of secondary pharmaceuticals. The drug repurposing and chiral-switches strategies have mostly been applied independently in drug discovery. Drug repurposing has peaked in the search for therapeutic treatments of the Coronavirus Disease 2019 pandemic, whereas chiral switches have been overlooked. The current Perspective introduces the drug repurposing/chiral-switches combination strategy, overviewing representative cases of chiral drugs that have undergone this combination: ketamine, flurbiprofen, fenfluramine, and milnacipran. The deuterium-enabled chiral switches of racemic thalidomide analogs, a variation of the repurposing/chiral-switch combination strategy, is also included. Patenting and regulatory-exclusivity considerations of the combination strategy in the discovery of new medical uses are considered. The proposed combination creates a new synergy of its two elements, overcoming arguments against chiral switches, with better prospects for validation of patents and regulatory exclusivities. The combination strategy may be applied to chiral switches to paired enantiomers. Repurposing/chiral-switch drugs may be 'obvious-to-try'; however, their inventions may be unexpected and their patents nonobvious. Patenting repurposing/chiral-switch combination drugs is not 'evergreening', 'product hopping', and 'me-too'. The expected benefits and opportunities of the combined repurposing/chiral-switch strategy vis-à-vis its two elements are superior pharmacological properties, overcoming arguments against patent validities, challenges of chiral-switch patents, reduced expenses, shortened approval procedures, and higher expectations of regulatory exclusivities.

| S-EPMC9926527 | biostudies-literature

Design of Fluorine-Containing 3,4-Diarylfuran-2(5H)-ones as Selective COX-1 Inhibitors.

Project description:We report the design and synthesis of fluorine-containing cyclooxygenase-1 (COX-1)-selective inhibitors to serve as prototypes for the development of a COX-1-targeted imaging agent. Deletion of the SO2CH3 group of rofecoxib switches the compound from a COX-2- to a COX-1-selective inhibitor, providing a 3,4-diarylfuran-2(5H)-one scaffold for structure-activity relationship studies of COX-1 inhibition. A wide range of fluorine-containing 3,4-diarylfuran-2(5H)-ones were designed, synthesized, and tested for their ability to selectively inhibit COX-1 in purified protein and human cancer cell assays. Compounds containing a fluoro-substituent on the C-3 phenyl ring and a methoxy-substituent on the C-4 phenyl ring of the 3,4-diarylfuran-2(5H)-one scaffold were the best COX-1-selective agents of those evaluated, exhibiting IC50s in the submicromolar range. These compounds provide the foundation for development of an agent to facilitate radiologic imaging of ovarian cancer expressing elevated levels of COX-1.

| S-EPMC4233350 | biostudies-literature

Synthesis of Deuterated Benzopyran Derivatives as Selective COX-2 Inhibitors with Improved Pharmacokinetic Properties.

Project description:We designed a series of specifically deuterated benzopyran analogues as new COX-2 inhibitors with the aim of improving their pharmacokinetic properties. As expected, the deuterated compounds retained potency and selectivity for COX-2. The new molecules possess improved pharmacokinetic profiles in rats compared to their nondeuterated congeners. Most importantly, the new compounds showed pharmacodynamic efficacy in several murine models of inflammation and pain. The benzopyran derivatives were separated into their enantiomers, and the activity was found to reside with the S-isomers. To streamline the synthesis of the desired S-isomers, an organocatalytic asymmetric domino oxa-Michael/aldol condensation reaction was developed for their preparation.

| S-EPMC4190635 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data