Recent Progress in Selective COX-2 Inhibitor Formulations and Therapeutic Applications - A Patent Review (2012-2022).

INTRODUCTION: Cyclooxygenase (COX), in literature, known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme that is responsible for the formation of prostanoids, including thromboxane and prostaglandins from arachidonic acid. COX-1 does housekeeping activity, whereas COX- 2 induces inflammation. Continuous rise in COX-2 gives birth to chronic pain-associated disorders, i.e., arthritis, cardiovascular complications, macular degeneration, cancer, and neurodegenerative disorders. Despite their potent anti-inflammatory effects, the detrimental effects of COX-2 inhibitors coexist in healthy tissues. Non-preferential NSAIDs cause gastrointestinal discomfort, whereas selective COX-2 inhibitors exert higher cardiovascular risk and renal impairment on chronic use. METHODS: This review paper covers key patents published between 2012-2022 on NSAIDs and coxibs, highlighting their importance, mechanism of action, and patents related to formulation and drug combination. So far, several drug combinations with NSAIDS have been used in clinical trials to treat chronic pain besides combating the side effects. CONCLUSION: Emphasis has been given on the formulation, drug combination, administration routesmodification, and alternative routes, i.e., parenteral, topical, and ocular DEPOT, improving its riskbenefit ratio of NSAIDs to improvise their therapeutic availability and minimize the adverse effects. Considering the wide area of research on COX-2 and ongoing studies, and future scope of view for the better use of the NSAIDs in treating debilitating disease-associated algesia.

Structural Perspectives and Advancement of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes.

Diabetes mellitus is an ailment that affects a large number of individuals worldwide and its pervasiveness has been predicted to increase later on. Every year, billions of dollars are spent globally on diabetes-related health care practices. Contemporary hyperglycemic therapies to rationalize Type 2 Diabetes Mellitus (T2DM) mostly involve pathways that are insulin-dependent and lack effectiveness as the pancreas' ß-cell function declines more significantly. Homeostasis via kidneys emerges as a new and future strategy to minimize T2DM complications. This article covers the reabsorption of glucose mechanism in the kidneys, the functional mechanism of various Sodium- Glucose Cotransporter 2 (SGLT2) inhibitors, their structure and driving profile, and a few SGLT2 inhibitors now accessible in the market as well as those in different periods of advancement. The advantages of SGLT2 inhibitors are dose-dependent glycemic regulation changes with a significant reduction both in the concentration of HbA1c and body weight clinically and statistically. A considerable number of SGLT2 inhibitors have been approved by the FDA, while a few others, still in preliminaries, have shown interesting effects.

A review upon medicinal perspective and designing rationale of DPP-4 inhibitors.

Type 2 Diabetes Mellitus (T2DM) is one of the highly prevalence disorder and increasing day by day worldwidely. T2DM is a metabolic disorder, which is characterized by deficiency in insulin or resistance to insulin and thus increases the glucose levels in the blood. Various approaches are there to treat diabetes but still there is no cure for this disease. DPP-4 inhibitor is a privileged target in the field of drug discovery and provides various opportunities in exploring this target for development of molecules as antidiabetic agents. DPP-4 acts by inhibiting the incretin action and thus decreases the level of blood glucose by imparting minimal side effects. Sitagliptin, vildagliptin, linagliptin etc. are the different DPP-4 based drugs approved throughout the world for the treatment of diabetes mellitus. Cyanopyrrolidines, triazolopiperazine amide, pyrrolidines are basic core nucleus present in various DPP-4 inhibitors and has potential effects. In the past few years, researchers had applied various approaches to synthesize potent DPP-4 inhibitors as antidiabetic agent without side effects like weight gain, cardiovascular risks, retinopathy etc. This review will also emphasize the recent strategies and rationale utilized by researchers for the development of DPP-4 inhibitors. This review also reveals about the various other approaches like molecular modelling, ligand based drug designing, high throughput screening etc. are used by the various research group for the development of potential DPP-4 inhibitors.

Herbal Medicines for Diabetes Management and its Secondary Complications.

Diabetic Mellitus (DM) is a metabolic disorder that is concerning for people all over the world. DM is caused due to lack of insulin or ineffective production of insulin in the pancreas. A total of 463 million people were reported to have diabetes mellitus in 2019 and this number is predicted to rise up to 578 million by the year 2030 and 700 million by 2045. High blood sugar gives rise to many complications like diabetic retinopathy, diabetic nephropathy, atherosclerosis, hypercoagulability, cardiovascular disease, coronary heart disease, abdominal obesity, hypertension, hyperlipidemia, cerebrovascular disease, coronary artery disease, foot damage, skin complications, Alzheimer's disease, hearing impairment, and depression. These life-threatening complications make diabetes more severe than other diseases. Many synthetic drugs have been developed, but still, a complete cure is not provided by any of the molecules. Continuous use of some synthetic agents causes severe side effects, and thus the demand for non-toxic, affordable drugs still persists. Traditional treatments have been an extremely valued source of medicine all over human history. These are extensively used throughout the world, indicating that herbs are a growing part of modern and high-tech medicines. The World Health Organization (WHO) has listed a total of 21,000 plants, which are used for medicinal purposes around the world. Among them, more than 400 plants are available for the treatment of diabetes. Despite the fact that there are many herbal drugs available for treating diabetes, only a small number of these plants have undergone scientific and medical evaluation to assess their efficacy. Trigonella foenum-graecum, Allium sativum, Caesalpinia bonduc, Ferula assafoetida,etc., are some of the medicinal plants used for antidiabetic therapy. The presence of phenolic compounds, flavonoids, terpenoids, and coumarins is responsible for the antidiabetic nature of the medicinal plants. These constituents have shown a reduction in blood glucose levels. Pycnogenol, acarbose, miglitol, and voglibose are some of the examples of marketed drugs, which are obtained from natural origin and used as antidiabetic drugs. The active principles derived from the plants work through many antidiabetic mechanisms, which include inhibition of α-glucosidase, α-amylase, and protein tyrosine phosphatase 1B activities. One of the major advantages of herbal drugs is the low level of side effects attributed to these medicines, and this attracted various researchers to develop new molecules for the treatment of diabetes. In this review, recent advances in the field of herbal drugs to treat diabetes, prevent secondary complications from arising due to diabetes, and various herbal molecules in different stages of clinical trials will be emphasized upon.

2, 3-Diaryl-5-ethylsulfanylmethyltetrahydrofurans as a new class of COX-2 inhibitors and cytotoxic agents.

2,3-Diaryl-5-ethylsulfanylmethyltetrahydrofuran-3-ols were designed and synthesized by the allylations of benzoins followed by iodocyclization and nucleophilic replacement reactions with ethanthiol. These molecules exhibit IC(50) for COX-2 at <10 nM concentration and exhibit average GI(50) over all the 59 human tumor cell lines at microM concentration.

2,3,5-Substituted tetrahydrofurans: COX-2 inhibitory activities of 5-hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols.

5-Hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols have been investigated for their COX-1 and COX-2 inhibitory activities. Compounds 17, 18 and 20 have been identified as showing appreciable COX-2 inhibition and selectivity. The group present at C-5 of tetrahydrofuran and the substituents at the two phenyl rings, through their interactions with active site amino acid residues, significantly affect the activities of these molecules. The quantitative structure-activity relationship studies indicate the role of logP, TPSA, molecular connectivity and valence connectivity towards the activities of these molecules.

Current status of COX-2 inhibitors.

The two isoforms of enzyme cyclooxygenase viz. COX-1 and COX-2 play key roles in the metabolism of arachidonic acid. The enzyme COX-2, when over expressed, leads to more production of prostaglandins causing inflammation and it also participates in the propagation of cancer. Therefore, COX-2 becomes the cellular target of a number of chemical entities for the treatment of inflammatory diseases as well as for the chemotherapy of cancer. In the present review, an up to date status of the compounds investigated for COX-2 inhibition has been given so that a collective view of the existing COX-2 inhibitors could be helpful for the design of safer anti-inflammatory drugs. In order to cover the maximum reported COX-2 inhibitors, a unique classification on the basis of the central core of the molecule (carrying mostly the phenyl moieties) has been followed, an outline of which has been given below: [structure: see text]. Each category of compounds has been discussed with suitable examples giving the IC(50) (for COX-2) values and the selectivity towards COX-2 over COX-1 of most potent compounds.

1-Toluene-sulfonyl-3-[(3'-hydroxy-5'-substituted)-gamma-butyrolactone]-indoles: synthesis, COX-2 inhibition and anti-cancer activities.

Indoles carrying a cyclic ester (gamma-butyrolactone) at C-3 position have been synthesized by the allylation of 3-indoleglyoxylate followed by iodocyclisation and the nucleophilic replacement of the iodo-group. Screening of these molecules for COX-2 inhibition and anti-cancer activities has identified compounds 10 and 11 as highly potent and selective for COX-2 as well as showing remarkable anti-cancer activities (better than that of indomethacin).

2,3,5-Substituted tetrahydrofurans as cancer chemopreventives. Part 1: synthesis and anti-cancer activities of 5-hydroxymethyl-2,3-diaryl-tetrahydro-furan-3-ols.

The allylation of appropriate benzoin in presence of indium metal followed by m-CPBA mediated cyclization gave 5-hydroxymethyl-2,3-diaryl-tetrahydro-furan-3-ols. Investigations on 59 human tumor cell lines of these compounds identify four compounds exhibiting significant growth inhibition of tumor cells at particular cell lines. Compound 12 is very specific toward CCRF-CEM and SR cell lines of leukemia.

5-Substituted-2,3-diphenyltetrahydrofurans: a new class of moderately selective COX-2 inhibitors.

The nature of C-5 substituent and the configuration at C-5 carbon of 2,3-diphenyltetrahydrofurans, with chiral centres at C-2, C-3 and C-5, show a remarkable influence on their COX-2 inhibition and selectivity. Out of the eight compounds investigated here, 1b with COOH group and R* configuration at C-5, and 2d with CH2SCH2CH3 group and S* configuration at C-5 have been identified as lead molecules for further studies on COX-2 inhibition.