Identification and biological activity of 6-alkyl-substituted 3-methyl-pyridine-2-carbonyl amino dimethyl-benzoic acid EP4 antagonists

Blanco, Marı́a-Jesús; Vetman, Tatiana; Chandrasekhar, Srinivasan; Fisher, M.; Kuklish, Steven L.; Chambers, M.G.; Lin, Chaohua; Mudra, Daniel R.; Oskins, J.L.; Wang, Xu-Shan; Yu, Xiaopeng; Warshawsky, Alan M.

doi:10.1016/j.bmcl.2016.03.041

Cited by 10 publications

(14 citation statements)

References 20 publications

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“…LY3127760 is a selective EP4 receptor antagonist that is structurally distinct from grapiprant . It demonstrated analgesic and anti‐inflammatory efficacy in a variety of preclinical models, including the rat monoiodoacetate model, an adjuvant arthritis model, and a rat plasma protein extravasation model for migraine headaches . A combined single (unpublished data, Lilly and Company) and multiple‐ascending dose study was conducted to evaluate the safety and tolerability of LY3127760 in healthy subjects.…”

mentioning

confidence: 99%

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

Jin

Smith

et al. 2017

Clinical Translational Sci

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Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator‐blind, parallel‐group, multiple‐ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose‐dependent blockade of the EP4 receptor. Compared with placebo, 24‐h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070.

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confidence: 99%

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

Jin

Smith

et al. 2017

Clinical Translational Sci

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“…It has been reported that LY3127760 had therapeutic effects on animal models of monoiodoacetate‐induced osteoarthritis, adjuvant arthritis, and migraine headache (Blanco et al. ). Based on these developments of EP4 antagonists for clinical use, inhibition of EP4 might be considered to be a potential therapeutic strategy for AAA.…”

Section: Discussionmentioning

confidence: 99%

“…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). Based on these developments of EP4 antagonists for clinical use, inhibition of EP4 might be considered to be a potential therapeutic strategy for AAA.…”

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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“…The off-target activity related to prostaglandin pathway (Table 2) were obtained at CEREP (Blanco et al 2016c).…”

Section: Off-target Activitymentioning

confidence: 99%

“…Recently, we have described several EP4 antagonists that are highly selective and potent (Blanco et al. ,b,c; Schiffler et al. ).…”

Section: Introductionmentioning

confidence: 99%

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

Chandrasekhar

Oskins

et al. 2017

Pharmacology Res & Perspec

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Prostaglandin (PG) E2 is the key driver of inflammation associated with arthritic conditions. Inhibitors of PGE 2 production (NSAIDs and Coxibs) are used to treat these conditions, but carry significant side effect risks due to the inhibition of all prostanoids that play important physiological function. The activities of PGE 2 are transduced through various receptor sub‐types. Prostaglandin E2 type 4 receptor (EP4) is associated with the development of inflammation and autoimmunity. We therefore are interested in identifying novel EP4 antagonists to treat the signs and symptoms of arthritis without the potential side effects of PGE 2 modulators such as NSAIDs and Coxibs. Novel EP4 antagonists representing distinct chemical scaffolds were identified using a variety of in vitro functional assays and were shown to be selective and potent. The compounds were shown to be efficacious in animal models of analgesia, inflammation, and arthritis.

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Identification and biological activity of 6-alkyl-substituted 3-methyl-pyridine-2-carbonyl amino dimethyl-benzoic acid EP4 antagonists

Cited by 10 publications

References 20 publications

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

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

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

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

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