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Overview on the Discovery and Development of Anti-Inflammatory Drugs: Should the Focus Be on Synthesis or Degradation
Gopa Mahesh1, Kotha Anil Kumar1, Pallu Reddanna1
1Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India.
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 PGE2 is the key mediator of inflammatory disorders, coming up with a strategy to reduce the levels of PGE2 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 PGE2-mPGES-1; PGE2 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 PGE2; and 3) the status of alternative targets being explored for the discovery and development of anti-inflammatory drugs without side-effects.
Insights
Conventional anti-inflammatory drugs cause side effects. New strategies focus on reducing prostaglandin E2 (PGE2) or targeting other pathways to develop safer anti-inflammatory drugs without adverse effects.
Area of Science:
- Pharmacology
- Immunology
- Drug Discovery
Background:
- Inflammation is a critical biological response to injury and infection, but chronic inflammation drives many diseases, including cancer.
- Cytokine storms, a severe inflammatory response, are implicated in mortality, notably in COVID-19 patients.
- Current anti-inflammatory drugs, like NSAIDs and COXIBs, target cyclooxygenase (COX) enzymes but cause significant gastric, renal, and cardiac side effects.
Purpose of the Study:
- To review the side effects associated with NSAIDs and COXIBs.
- To evaluate whether therapeutic strategies should target pathways upstream or downstream of prostaglandin E2 (PGE2).
- To explore alternative targets for developing novel anti-inflammatory drugs with improved safety profiles.
Main Methods:
- Review of existing literature on anti-inflammatory drug mechanisms, side effects, and emerging therapeutic targets.
- Analysis of the roles of prostaglandin E2 (PGE2) and leukotrienes in inflammatory processes.
- Examination of novel drug development strategies targeting PGE2 synthesis, degradation, receptor activity, or dual COX/LOX inhibition.
Main Results:
- NSAIDs and COXIBs exhibit dose-limiting toxicities due to non-selective inhibition of COX-1 and COX-2 or long-term cardiac risks.
- Targeting prostaglandin E2 (PGE2) alone, either by inhibiting its synthesis (e.g., mPGES-1), enhancing degradation (e.g., 15-PGDH), or blocking its receptor (EP4), presents a promising avenue.
- Dual inhibition of both cyclooxygenase (COX) and lipoxygenase (LOX) pathways is also being investigated for broader anti-inflammatory effects.
Conclusions:
- The development of next-generation anti-inflammatory drugs necessitates strategies that minimize side effects associated with current therapies.
- Focusing on modulating prostaglandin E2 (PGE2) metabolism or its downstream effects offers a potential path toward safer anti-inflammatory agents.
- Exploring alternative targets and combination therapies holds promise for achieving effective inflammation control without compromising patient safety.
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