LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles

Jin, Yan; Smith, Claire; Hu, Lei; Coutant, David E.; Whitehurst, Kelly; Phipps, Krista M; McNearney, Terry A.; Yang, Xiao Yan; Ackermann, Bradley L.; Pottanat, Thomas G.; Landschulz, William

doi:10.1111/cts.12497

Cited by 23 publications

(28 citation statements)

References 11 publications

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“…EP4 could represent a promising target to inhibit Th17 cell development in AS. Specific EP4 antagonists have been developed and their efficiency to inhibit Th17 cells has been tested in vitro [62][63][64]. Selective inhibition of EP4 could represent a promising strategy to reduce Th17 cell frequencies and disease activity in AS.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin receptor EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis

et al. 2019

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Background: Th17 cells are involved in the pathogenesis of ankylosing spondylitis (AS). However, the mechanism underlying enhanced Th17 cell accumulation in AS remains unknown. The prostaglandin E 2 receptor EP2/EP4 signaling pathway plays a critical role in the development of autoimmune Th17 cells. Interestingly, recent genomewide association studies (GWAS) have identified five risk alleles for AS in PTGER4, the gene encoding for EP4. The aim of this study was to reveal a possible link between EP4 and disease activity in patients with AS. Methods: Th17 cells from patients with AS were analyzed for the transcriptional expression of prostaglandin receptor genes by quantitative RT-PCR. Th17 cells from patients with rheumatoid arthritis (RA) and from healthy individuals served as controls. EP4 receptor expression in Th17 cells was assessed ex vivo by flow cytometry and by western blot. Functional analysis using EP4-specific agonists was performed to reveal how EP4 regulates Th17 cells. Results: EP4 is significantly overexpressed in Th17 cells from patients with AS compared to Th17 cells from healthy individuals or patients with RA or psoriatic arthritis (PsA). EP4 upregulation is unique to Th17 cells and is not found in other CD4 + T cell subsets. Specific activation of EP4 drives Th17 cell development and promotes EP4 expression in a positive feedback loop in AS but not in RA or PsA. Mechanistically, EP4 acts via upregulation of the interleukin-23 receptor (IL-23R), by suppressing the RORγt inhibitor FoxO1 and by enhancing STAT3 phosphorylation. Increased EP4 expression levels in Th17 cells from AS patients correlate with high disease activity as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4 (r = 0.7591, p = 0.0016). Conclusions: EP4 is a potential marker of disease activity in patients with AS. Aberrant EP4 expression might contribute to pathogenic Th17 cell accumulation and represent a new target for the treatment of AS.

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Section: Discussionmentioning

confidence: 99%

Prostaglandin receptor EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis

et al. 2019

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“…Application of the asymmetric sp 2 -sp 3 Suzuki-Miyaura methodology [22] enabled the synthesis of clinical candidates preclamol (15, a dopamine D2 receptor partial agonist studied for the treatment of schizophrenia), niraparib (16, MK−4827, a 2017 approved poly-(ADP ribose) polymerase (PARP) inhibitor indicated for ovarian cancer), and natural product isoanabasine (17), which are all presented in Figure 3 with their corresponding Fsp 3 values calculated using SwissADME [23] online tool. An example of the trend to increase Fsp 3 during the Lead Optimization phase, leveraging crosscoupling reactions in drug design, comes from the evolution of the SAR approach for novel Eprostanoid receptor 4 (EP4) antagonists ( Figure 4) [24,25] that eventually led to the discovery of LY3127760 [26]. An initial lead (naphthalene derivative, 18) [27] was identified through an early medicinal chemistry effort, possessing modest human whole blood activity (hWB, IC50 = 243 nM) and low Fsp 3 .…”

Section: C-c Reaction: Suzuki-miyaura Reactionmentioning

confidence: 99%

Impact of Cross-Coupling Reactions in Drug Discovery and Development

2020

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Cross-coupling reactions have played a critical role enabling the rapid expansion of structure–activity relationships (SAR) during the drug discovery phase to identify a clinical candidate and facilitate subsequent drug development processes. The reliability and flexibility of this methodology have attracted great interest in the pharmaceutical industry, becoming one of the most used approaches from Lead Generation to Lead Optimization. In this mini-review, we present an overview of cross-coupling reaction applications to medicinal chemistry efforts, in particular the Suzuki–Miyaura and Buchwald–Hartwig cross-coupling reactions as a remarkable resource for the generation of carbon–carbon and carbon–heteroatom bonds. To further appreciate the impact of this methodology, the authors discuss some recent examples of clinical candidates that utilize key cross-coupling reactions in their large-scale synthetic process. Looking into future opportunities, the authors highlight the versatility of the cross-coupling reactions towards new chemical modalities like DNA-encoded libraries (DELs), new generation of peptides and cyclopeptides, allosteric modulators, and proteolysis targeting chimera (PROTAC) approaches.

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“…The selective EP4 antagonist grapiprant has been approved for the treatment of osteoarthritis pain in dogs (Rausch-Derra et al 2016). Recently, a clinical study demonstrated that the selective EP4 antagonist LY3127760 at daily doses of 60 mg to 600 mg was safe and tolerable in healthy subjects during oral dosing for 28 days (Jin et al 2018). It has been reported that LY3127760 had therapeutic effects on animal models of monoiodoacetate-induced osteoarthritis, adjuvant arthritis, and migraine headache (Blanco et al 2016).…”

Section: Discussionmentioning

confidence: 99%

A selective antagonist of prostaglandin E receptor subtype 4 attenuates abdominal aortic aneurysm

Yokoyama

Saito

et al. 2018

Physiol Rep

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Abdominal aortic aneurysm (AAA) is a progressive disease that has an increasing prevalence with aging, but no effective pharmacological therapy to attenuate AAA progression is currently available. We reported that the prostaglandin E receptor EP4 plays roles in AAA progression. Here, we show the effect of CJ‐42794, a selective EP4 antagonist, on AAA using two mouse models (angiotensin II‐ and CaCl2‐induced AAAs) and human aortic smooth muscle cells isolated from AAA tissue. Oral administration of CJ‐42794 (0.2 mg/kg per day) for 4 weeks significantly decreased AAA formation in ApoE−/− mice infused with angiotensin II (1 μg/kg per min), in which elastic fiber degradation and activations of matrix metalloproteinase (MMP)‐2 and MMP‐9 were attenuated. Interleukin‐6 (IL‐6) proteins were highly expressed in the medial layer of angiotensin II‐induced mouse AAA tissues, whereas this expression was significantly decreased in mice treated with CJ‐42794. AAA formation induced by periaortic CaCl2 application in wild‐type mice was also reduced by oral administration of CJ‐42794 for 4 weeks. After oral administration of CJ‐42794 beginning 2 weeks after periaortic CaCl2 application and continuing for an additional 4 weeks, the aortic diameter and elastic fiber degradation grade were significantly smaller in CJ‐42794‐treated mice than in untreated mice. Additionally, in smooth muscle cells isolated from human AAA tissues, stimulation of CJ‐42794 inhibited PGE 2‐induced IL‐6 secretion in a dose‐dependent manner and decreased PGE 2‐induced MMP‐2 activity. These data suggest that inhibition of EP4 has the potential to be a pharmacological strategy for attenuation of AAA progression.

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LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles

Cited by 23 publications

References 11 publications

Prostaglandin receptor EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis

Prostaglandin receptor EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis

Impact of Cross-Coupling Reactions in Drug Discovery and Development

A selective antagonist of prostaglandin E receptor subtype 4 attenuates abdominal aortic aneurysm

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