The discovery of acetylsalicylic acid

The discovery of acetylsalicylic Diphenyleneiodonium chloride (aspirin) in 1897 paved the way for the development of classical NSAIDs as first-line therapeutics for anti-inflammatory, anti-pyretic and analgesic therapy. Large efforts have been made in the following decades to improve the efficacy and in particular safety of this first-generation of NSAIDs, but the success remained limited. Along with better understanding of the pleiotropic pathophysiological and homeostatic mechanisms that orchestrate inflammation came also the insight that the moderate interference with multiple targets might have advantages compared to single-target drugs in re-adjusting homeostasis. Many attempts have been made to target eicosanoid biosynthesis, in particular COX-dependent PGE2 and 5-LO-dependent LT biosynthesis. Since natural products represent rich sources of privileged structures that share multiple bioactivities, the interest in exploring their impact on human physiology increased. In particular, plant-derived remedies often display anti-inflammatory properties, at least in experimental studies, with multiple modes of action, and they are often preferred by patients with chronic inflammatory disorders over NSAIDs and glucocorticoids due to fewer side effects. The transfer of the acquired insights into straightforward anti-inflammatory multi-target drug development was often hampered by an insufficient knowledge about the key players in eicosanoid biosynthesis, which rendered the selection of safe and efficient target combinations difficult. The methodological advances in chromatography and mass spectrometry-based lipidomics and the reconsideration of eicosanoids as equally pro-inflammatory, homeostatic and pro-resolving mediators opened the door into a new universe of multi-target strategies with dual inhibitors of mPGES-1 and 5-LO product formation at the forefront. Major challenges are still the design of potent dually acting candidates with favorable selectivity profile, bioavailability and pharmacokinetics. Diverse remedies (e.g., frankincense, cannabis, St. John's wort) and isolated natural products (e.g., curcumin, EGCG, carnosol and carnosic acid) from plant origin are commonly used in inflammation therapy, and dual inhibition of the formation of PGE2 and LTs may provide a rational for their anti-inflammatory features. In fact, these and additional agents such as the acylphloroglucinols MC-A, arzanol, garcinol, and acrovestones, as well as lichen depsides and depsidones or embelin proved as valuable sources for structurally diverse drug-like leads that combine high-affinities for mPGES-1, 5-LO and/or FLAP with low-affinity inhibition of other targets including COX-1. The field of natural products that dually interfere with LT and PGE2 formation will certainly benefit from future approaches that focus on rigorous proof-of-concept studies in vivo along with pharmacokinetics analysis demanding the same high standards as for NSAIDs or synthetic dual 5-LO/mPGES-1 inhibitors. For instance, bioavailability and pharmacokinetic properties (i.e., water solubility, absorption, metabolic stability, plasma protein binding) after oral application are additional aspects that for most of the presented natural products have not been thoroughly studied and clinical trials have not yet been performed. For some compounds (e.g., curcumin or EGCG) the available data even indicate poor physicochemical and pharmacokinetic features with limited perspective for efficient therapeutic use. Moreover, results from clinical trials with natural products (e.g., extracts from willow bark, nettle, devil's claw, etc.) are often insufficient to validate their efficacy in inflammatory or painful disorders like osteoarthritis, rheumatoid arthritis, or back pain, questioning the therapeutic value of such phytomedicine. On the other hand, encouraging results from a recent phase IIa clinical trial with an orally applied frankincense extract that reduced disease activity in relapsing-remitting multiple sclerosis (Sturner et al., 2017) clearly underline the therapeutic potential of anti-inflammatory natural products. Taken together, the time has come to use the profound knowledge from mechanism-based natural medicine and compound-oriented pre-clinical studies on mPGES-1/5-LO-dually acting natural products and their semi-synthetic derivatives to proceed to clinical trials. The future of this new generation of anti-inflammatory drugs will essentially depend on whether they fulfill the high expectations in efficacy and especially safety in direct comparison to NSAIDs.