Analgesic and anti‐inflammatory properties of novel, selective, and potent EP4 receptor antagonists

Chandrasekhar, Srinivasan; Yu, Xiaopeng; Oskins, J.L.; Lin, Chaohua; Wang, Xushan; Blanco, Marı́a-Jesús; Fisher, M.; Kuklish, Steven L.; Schiffler, Matthew A.; Vetman, Tatiana; Warshawsky, Alan M.; York, Jeremy S.; Bendele, Alison M.; Chambers, M.G.

doi:10.1002/prp2.316

Cited by 14 publications

(8 citation statements)

References 41 publications

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“…PGE 2 and its downstream effectors are potential targets for modulation of inflammation associated with OA (31,34). This randomized, double-blind, placebo-and active-controlled, multicenter clinical study investigated the efficacy of an mPGES1 inhibitor (LYA) and an EP4 antagonist (LYB) for the treatment of chronic OA pain and was designed to inform drug development for both human and animal health.…”

Section: Discussionmentioning

confidence: 99%

“…PGE 2 exerts its biological effects by binding to four specific membrane-bound G protein-coupled receptors [EP1 (E-type prostanoid 1) to EP4]. Of the four receptors, EP4 is associated with the development of inflammation and autoimmunity and is not known to be associated with the direct modulation of other prostanoids (31). In 2016, a PGE 2 EP4 receptor antagonist (grapiprant) was approved for use in dogs, representing the first demonstration of efficacy for this new class of piprant drugs (32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

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A randomized clinical efficacy study targeting mPGES1 or EP4 in dogs with spontaneous osteoarthritis

et al. 2019

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Canine studies of spontaneous osteoarthritis (OA) pain add valuable data supporting drug treatment mechanisms that may translate to humans. A multicenter, randomized, double-blind, placebo- and active-controlled study was conducted in client-owned dogs with moderate OA pain to evaluate efficacy of LYA, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES1), an EP4 antagonist (LYB), and carprofen, versus placebo. Of 255 dogs screened, 163 were randomized (placebo/LYA/LYB/carprofen: n = 43/39/42/39) and 158 completed treatment. Efficacy versus placebo was assessed using Bayesian mixed-effect model for repeated measure analyses of the Canine Brief Pain Inventory (CBPI) pain interference score (PIS; primary endpoint), pain severity score, and overall impression, as well as the Liverpool Osteoarthritis in Dogs (LOAD) mobility score. The posterior probability that the difference to placebo was <0 at week 2 was 80% for LYA and 54% for LYB for CBPI PIS (both <95% predefined threshold). For secondary endpoints, the posterior probability that the difference to placebo was <0 at week 2 ranged from 89 to 96% for LYA and from 56 to 89% for LYB. The posterior probabilities comparing carprofen to placebo groups were ≥90% for all efficacy endpoints. The proportion of dogs with one or more adverse event was not significantly different from placebo (32.6%) for LYA (35.9%) or carprofen (25.6%), but the rate for LYB (59.5%) was higher versus placebo (P = 0.017). LYA treatment demonstrated consistent improvement in all efficacy measures, suggesting that inhibition of mPGES1 may be an effective treatment for chronic pain associated with OA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A randomized clinical efficacy study targeting mPGES1 or EP4 in dogs with spontaneous osteoarthritis

et al. 2019

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“…More recently, experimental data in cellular and animal models have outlined a far more interesting pharmacological profile for selective EP4 receptor antagonists [ 11 , 41 ]. Whether they may offer an advantage as simple analgesics over existing drugs such as COX inhibitors is still unclear.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological characterisation of CR6086, a potent prostaglandin E2 receptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug

Caselli¹,

Bonazzi²,

Lanza³

et al. 2018

Arthritis Res Ther

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BackgroundProstaglandin E2 (PGE2) acts via its EP4 receptor as a cytokine amplifier (e.g., interleukin [IL]-6) and induces the differentiation and expansion of inflammatory T-helper (Th) lymphocytes. These mechanisms play a key role in the onset and progression of rheumatoid arthritis (RA). We present the pharmacological characterisation of CR6086, a novel EP4 receptor antagonist, and provide evidence for its potential as a disease-modifying anti-rheumatic drug (DMARD).MethodsCR6086 affinity and pharmacodynamics were studied in EP4-expressing HEK293 cells by radioligand binding and cyclic adenosine monophosphate (cAMP) production, respectively. In immune cells, IL-6 and vascular endothelial growth factor (VEGF) expression were analysed by RT-PCR, and IL-23 and IL-17 release were measured by enzyme-linked immunosorbent assay (ELISA). In collagen-induced arthritis (CIA) models, rats or mice were immunised with bovine collagen type II. Drugs were administered orally (etanercept and methotrexate intraperitoneally) starting at disease onset. Arthritis progression was evaluated by oedema, clinical score and histopathology. Anti-collagen II immunoglobulin G antibodies were measured by ELISA.ResultsCR6086 showed selectivity and high affinity for the human EP4 receptor (Ki = 16.6 nM) and functioned as a pure antagonist (half-maximal inhibitory concentration, 22 nM) on PGE2-stimulated cAMP production. In models of human immune cells in culture, CR6086 reduced key cytokine players of RA (IL-6 and VEGF expression in macrophages, IL-23 release from dendritic cells, IL-17 release from Th17 cells). In the CIA model of RA in rats and mice, CR6086 significantly improved all features of arthritis: severity, histology, inflammation and pain. In rats, CR6086 was better than the selective cyclooxygenase-2 inhibitor rofecoxib and at least as effective as the Janus kinase inhibitor tofacitinib. In mice, CR6086 and the biologic DMARD etanercept were highly effective, whereas the non-steroidal anti-inflammatory drug naproxen was ineffective. Importantly, in a study of CR6086/methotrexate, combined treatment greatly improved the effect of a fully immunosuppressive dose of methotrexate.ConclusionsCR6086 is a novel, potent EP4 antagonist showing favourable immunomodulatory properties, striking DMARD effects in rodents, and anti-inflammatory activity targeted to immune-mediated inflammatory diseases and distinct from the general effects of cyclooxygenase inhibitors. These results support the clinical development of CR6086, both as a stand-alone DMARD and as a combination therapy with methotrexate. The proof-of-concept trial in patients with RA is ongoing.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1537-8) contains supplementary material, which is available to authorized users.

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“…To the contrary, another study showed that PGE2 inhibited IL-1b-induced expression of MMP1 and MMP13 via EP4 by suppressing MKK4-JNK MAPK-c-JUN pathway in human chondrocytes (127). Furthermore, the EP4 receptor mediates the PGE2-elicited inflammation and sensitization of sensory neurons, while EP4 inhibition contributes to the development of targeted therapies for antiinflammatory and analgesic effect in OA (128)(129)(130)(131). Grapiprant, an EP4 antagonist, has been approved for by the FDA treating OA pain in dogs (132,133).…”

Section: Prostaglandin Receptorsmentioning

confidence: 99%

G Protein-Coupled Receptors in Osteoarthritis

et al. 2022

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Osteoarthritis (OA) is the most common chronic joint disease characterized, for which there are no available therapies being able to modify the progression of OA and prevent long-term disability. Critical roles of G-protein coupled receptors (GPCRs) have been established in OA cartilage degeneration, subchondral bone sclerosis and chronic pain. In this review, we describe the pathophysiological processes targeted by GPCRs in OA, along with related preclinical model and/or clinical trial data. We review examples of GPCRs which may offer attractive therapeutic strategies for OA, including receptors for cannabinoids, hormones, prostaglandins, fatty acids, adenosines, chemokines, and discuss the main challenges for developing these therapies.

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Analgesic and anti‐inflammatory properties of novel, selective, and potent EP4 receptor antagonists

Cited by 14 publications

References 41 publications

A randomized clinical efficacy study targeting mPGES1 or EP4 in dogs with spontaneous osteoarthritis

A randomized clinical efficacy study targeting mPGES1 or EP4 in dogs with spontaneous osteoarthritis

Pharmacological characterisation of CR6086, a potent prostaglandin E2 receptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug

G Protein-Coupled Receptors in Osteoarthritis

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