Overview on the Discovery and Development of Anti-Inflammatory Drugs: Should the Focus Be on Synthesis or Degradation of PGE2?

Abstract

Inflammation is a protective response that develops against tissue injury and infection. Chronic inflammation, on the other hand, is the key player in the pathogenesis of many inflammatory disorders including cancer. The cytokine storm, an inflammatory response flaring out of control, is mostly responsible for the mortality in COVID-19 patients. Anti-inflammatory drugs inhibit cyclooxygenases (COX), which are involved in the biosynthesis of prostaglandins that promote inflammation. The conventional non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastric and renal side-effects, as they inhibit both the constitutive COX-1 and the inducible COX-2. The majority of selective COX-2 inhibitors (COXIBs) are without gastric side-effects but are associated with cardiac side-effects on long-term use. The search for anti-inflammatory drugs without side-effects, therefore, has become a dream and ongoing effort of the Pharma companies. As PGE 2 is the key mediator of inflammatory disorders, coming up with a strategy to reduce the levels of PGE 2 alone without affecting other metabolites may form a better choice for the development of next generation anti-inflammatory drugs. In this direction the options being explored are on synthesis of PGE 2 -mPGES-1; PGE 2 degradation through a specific PG dehydrogenase, 15-PGDH, and by blocking its activity mediated through a specific PGE receptor, EP4. As leukotrienes formed via the 5-lipoxygenase (5-LOX) pathway also play an important role in the mediation of inflammation, efforts are also being made to target both COX and LOX pathways. This review focuses on addressing the following three points: 1) How NSAIDs and COXIBs are associated with gastric, renal and cardiac side-effects; 2) Should the focus be on the targets upstream or downstream of PGE 2 ; and 3) the status of alternative targets being explored for the discovery and development of anti-inflammatory drugs without side-effects.

Interleukin-17A (IL-17A): A silent amplifier of COVID-19

“…The cytokine storm, and related cytokine release syndrome (CRS), can be considered as “an inflammatory response flaring out of control”, mostly responsible for the mortality in COVID-19 patients [9] , [10] , [11] . In this context, the potential role of IL-6 in COVID-19 pneumonia has provided a rationale for the investigation of IL-6 signalling inhibitor tocilizumab [12 ] .…”

Small molecule compounds with good anti-inflammatory activity reported in the literature from 01/2009 to 05/2021: a review

“…Therefore, it is of urgently significance to develop anti-inflammatory drugs with low toxicity and good efficacy. At present, the design of anti-inflammatory compounds has great limitations due to undesirable side effects but this has not curtailed enthusiasm of researchers in exploring for potent anti-inflammatory drugs 15 .…”

Different consequences of the treatment of osteoarthritis in gastrointestinal comorbidity with exocrine pancreatic insufficiency

“…The effectiveness of systemic and local NSAID use and the positive effect of NSAID use in patients with chronic pain was assessed [16][17][18]. Much attention has been paid to the investigation of the development of side effects with the use of NSAIDs [19][20][21][22][23][24]. The main side effects after NSAIDs which have been covered in many studies [25][26][27][28][29][30][31][32] are gastrointestinal disorders (nausea, vomiting, abdominal pain, diarrhea, constipation, flatulence, dyspepsia, dry mouth, peptic ulcers, bleeding, perforated ulcers, anorexia, elevated liver enzymes, pancreatic damage, and hepatic damage) [33][34][35][36][37]; neurological disorders (sleep disorders, anxiety, headache, dizziness, hot flashes, and paresthesia); disorders of the cardiovascular system (increased blood pressure, palpitations, tachycardia, hypotension, and peripheral edema) [38][39][40]; allergic complications (bronchospasm, shortness of breath, skin rash, the Stevens-Johnson and Lyell syndromes, photosensitization, anaphylactic reactions, facial edema, and itching) [41,42]; disorders of the genitourinary system (nephritis or nephrotic syndrome, polyuria, menstrual disorders in women, and disorders of the prostate in men) [39].…”