Structure-based discovery of mPGES-1 inhibitors suitable for preclinical testing in wild-type mice as a new generation of anti-inflammatory drugs

Abstract

Human mPGES-1 is recognized as a promising target for next generation of anti-inflammatory drugs without the side effects of currently available anti-inflammatory drugs, and various inhibitors have been reported in the literature. However, none of the reported potent inhibitors of human mPGES-1 has shown to be also a potent inhibitor of mouse or rat mPGES-1, which prevents using the well-established mouse/rat models of inflammation-related diseases for preclinical studies. Hence, despite of extensive efforts to design and discover various human mPGES-1 inhibitors, the promise of mPGES-1 as a target for the next generation of anti-inflammatory drugs has never been demonstrated in any wild-type mouse/rat model using an mPGES-1 inhibitor. Here we report discovery of a novel type of selective mPGES-1 inhibitors potent for both human and mouse mPGES-1 enzymes through structure-based rational design. Based on in vivo studies using wild-type mice, the lead compound is indeed non-toxic, orally bioavailable, and more potent in decreasing the PGE 2 (an inflammatory marker) levels compared to the currently available drug celecoxib. This is the first demonstration in wild-type mice that mPGES-1 is truly a promising target for the next generation of anti-inflammatory drugs.As the principal pro-inflammatory prostanoid, prostaglandin E2 (PGE 2 ) serves as a mediator of pain and fever in inflammatory reactions in a number of inflammation-related diseases 1 , such as chronic pains, cardiovascular diseases, neurodegenerative diseases, and cancers 2-4 . The biosynthesis 5 of PGE 2 starts from arachidonic acid (AA). Cyclooxygenase (COX)-1 or COX-2 converts AA to prostaglandin H2 (PGH 2 ) 5 , and prostaglandin E synthase (PGES) transforms PGH 2 to PGE 2 6 . The first generation of nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin used to treat pain and reduce fever or inflammation, inhibit both COX-1 and COX-2 without selectivity, and the second generation of NSAIDs, including celecoxib (Celebrex), rofecoxib (Vioxx) and valdecoxib (Bextra), selectively inhibit COX-2. The COX-2 specific inhibitors still have a number of serious side effects, such as increasing the risk of fatal heart attack or stroke and causing stomach or intestinal bleeding. The serious side effects led to withdrawal of rofecoxib and valdecoxib, although celecoxib still remains in clinical use. The serious side effects are due to the fact that the synthesis of all physiologically needed prostaglandins downstream of PGH 2 are inhibited by the action of the COX-1/2 inhibitors. For example, blocking the production of prostaglandin-I 2 (PGI 2 ) will cause significant cardiovascular problems 7 .Microsomal PGES-1 (mPGES-1), an inducible enzyme, is a more promising, ideal target for anti-inflammatory drugs, because the mPGES-1 inhibition will only block the PGE 2 production without affecting the production of

Biological characterization of new inhibitors of microsomal PGE synthase‐1 in preclinical models of inflammation and vascular tone

“…In summary, we have characterized, in the present study, five new cross‐species mPGES‐1 inhibitors suitable for p.o delivery with improved potency and selectivity compared to published inhibitors lacking interspecies differences (Ding et al, ; Leclerc, Idborg, et al, ; Leclerc, Pawelzik, et al, ). All five compounds presented comparable selectivity and potency.…”

“…We have previously characterized mPGES‐1 inhibitors lacking interspecies differences in murine models of inflammation (Leclerc, Idborg, et al, ; Leclerc, Pawelzik, et al, ) as well as in cancer models (Kock et al, ; Olesch et al, ) and recently Ding et al () described new cross‐species inhibitors, but there is still a need for further improved mPGES‐1 inhibitors for preclinical investigations. New mPGES‐1 inhibitors are required to have superior affinity and improved bioavailability.…”

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

“…Human mPGES-1 is recognized as a promising target for the next generation of anti-inflammatory drugs, without the side effects of those currently available (Ding et al, 2018). Our hypothesis, that selective mPGES-1 inhibition might attenuate COVID-19 associated disease symptoms, e.g.…”

“…Today mPGES-1 is considered as a potential safer target for anti-inflammatory drugs since it is only expressed in diseased tissues and downstream of the COX enzymes (Ding et al, 2018). COX enzymes are the current target of most commercially available non-steroidal anti-inflammatory drugs (NSAIDs, COX inhibitors).…”

The COX2 Effector Microsomal PGE2 Synthase 1 is a Regulator of Immunosuppression in Cutaneous Melanoma

“…It has been reported that both aspirin and celecoxib synergize with anti-PD-1 blockade in mouse models of melanoma and colorectal cancer (18). Comparisons between human, rat and mouse mPGES1 show structural differences in their active site that suggest more selective mouse inhibitors are needed to achieve the same degree efficacy when combined with PD-1 in a syngeneic mouse setting (47,48). This prompted us to perform KO of mPGES1 in syngeneic melanoma cells to achieve the same effects as aspirin or celecoxib.…”