The arachidonic acid (AA) cascade is an essential biochemical pathway that yields potent bioactive mediators contributing to various physiological and inflammatory conditions [1]. After being released from membrane phospholipids, AA is subjected to distinct enzymatic pathways involving cyclooxygenase (COX), lipoxygenases (LOX), and cytochrome P450s (CYP450), leading to the production of multiple series of essential lipid mediators (LM) such as prostaglandins (PGs), leukotrienes (LTs), lipoxins (LX), and epoxyeicosatrienoic acids (EETs), as illustrated in Fig. 1. Among them, PGE2 and LTs are associated with the evolvement and progression of chronic inflammatory diseases. Hence, substances aiming to inhibit the production of PGE2 and LTs by targeting COX-1/2 and 5-LOX, or 5-LOX activating protein (FLAP), respectively, are extensively investigated as potential therapeutic interventions for inflammatory disorders. Among these, nonsteroidal anti-inflammatory drugs (NSAIDs) targeting COX enzymes are commonly prescribed medications for the treatment of acute or chronic inflammatory diseases. However, since they also reduce the levels of PGs with homeostatic functions, they often cause severe gastrointestinal and cardiovascular side effects, limiting their clinical use for long-term treatments [2], [3]. In addition, selective interference of NSAIDs with the COX pathway may result in substrate redirection and amplification of alternative LM pathways, such as the 5-LOX pathway, leading to upregulated inflammatory LT levels, which may further increase the unwanted adverse effects [4], [5].

Recently, microsomal prostaglandin E2 synthase-1 (mPGES-1) functionally coupled with upstream COX-2 (Fig. 1) has emerged as an intriguing target alternative to COX enzymes [6], [7]. mPGES-1 catalyzes the formation of inflammatory PGE2 in concert with COX-2 at the terminus of the COX branch of the AA pathway and is markedly induced during inflammatory states with simultaneous upregulation of the preceding COX-2 enzyme that transforms AA to PGH2 (Fig. 1) [8].

Previous studies indicate that genetic deletion or inhibition of mPGES-1 with small molecules effectively suppresses inflammation, pain, and carcinogenesis in experimental animal models, highlighting the clinical potential of mPGES-1 as an attractive target for next-generation NSAID development [9], [10], [11]. Apparently, inhibition of the inducible mPGES-1 isoform may selectively interfere with the massive production of pro-inflammatory PGE2 to overcome the well-known adverse effects inherent to conventional NSAIDs, which are common inhibitors of PGE2 formation as well as of homeostatic prostanoid biosynthesis [4], [5]. Indeed, current findings from preclinical and clinical studies have confirmed that mPGES-1 inhibitors exert improved gastrointestinal and cardiovascular safety compared to traditional NSAIDs [9].

Despite consistent efforts targeting mPGES-1 over the past few decades, no mPGES-1 inhibitor has yet emerged in clinical practice. This appears to be because of the loss of potency of many inhibitors in human whole blood or the lack of potent inhibitors with interspecies activity, i.e., decreased potency towards mouse and rat enzymes [9], [12]. Given these particular hurdles, only a few inhibitors have been evaluated in human clinical trials so far (Fig. 2). The early inhibitors tested in humans include Eli Lilly compounds (1–2), but these studies were discontinued because of the drug-induced liver injury in several patients [13], [14]. Zaloglanstat (3) was another compound from Ichnos Sciences, which was enrolled in Phase I for arthritis (Clinical Trials Identifier: NCT02179645); however, no report has yet been published on the progress of this compound. Recently, it has been announced that Gesyntha's Vipoglanstat (GS-248, 4) is in Phase II for the treatment of Raynaud's disease and systemic sclerosis (Clinical Trials Identifier: NCT04744207).

Our group has been intensively working on the development of novel anti-inflammatory agents via multi-targeting approaches within the AA cascade, including mPGES-1 and 5-lipoxygenase-activating protein (FLAP) [6], [15], [16], [17], [18], [19]. Our findings allowed us to broaden the compound collection with the intent of improving affinity for mPGES-1 to find new potential chemotypes. In this regard, the reported anti-inflammatory potential and synthetic feasibility of oxadiazole derivatives [20], [21], [22] encouraged us to introduce 1,3,4-oxadiazole as a central core for designing new analogs, which resulted in selective and potent inhibition of mPGES-1 activity at one-digit nanomolar concentrations.