Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandin e synthase 1 inhibitor, with celecoxib

Jin, Yan; Smith, C. Wayne; Hu, Lei; Campanale, Kristina M.; Stoltz, Randall; Huffman, LG; McNearney, T. A.; Xy, Yang; Bl, Ackermann; Dean, Robert A.; Regev, Arie; Landschulz, William

doi:10.1002/cpt.260

Cited by 59 publications

(48 citation statements)

References 18 publications

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“…(38, 39) Pharmacological inhibition of mPGES-1 in humans has also been shown to increase production of PGI 2 and TXA 2 . (40) Our current findings show that inhibition of mPGES-1 in hASMCs with 0.1 or 1 µM 15d-PGJ 2 resulted in a significant increase in the detection of the stable PGI 2 product 6-keto PG F1α, whereas the higher concentration of 10 µM significantly reduced 6-keto PG F1α levels (Figure 4E). In contrast, only the highest concentration of 10 µM 15d-PGJ 2 produced a significant increase in the level of the stable TXA 2 product TXB 2 (Figure 4F).…”

Section: Resultssupporting

confidence: 53%

“…(38) Pharmacological inhibition of mPGES-1 in humans has also been shown to increase production of PGI 2 and TXA 2 . (40) Our current finding show that at the lower concentrations of mPGES-1 inhibitor treatment, PGI 2 significantly increased, whereas the highest concentration significantly reduced PGI 2 levels (Figure 4E). Furthermore, the mPGES-1 siRNA transfection produced effects similar to the highest concentration of the mPGES-1 inhibitor.…”

Section: Discussionsupporting

confidence: 56%

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Microsomal Prostaglandin E Synthase-1 Expression by Aortic Smooth Muscle Cells Attenuates the Differentiated Phenotype

Adedoyin

Loftin²

2016

Journal of Cardiovascular Pharmacology

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The development of numerous types of cardiovascular disease is associated with alteration of the vascular smooth muscle cell (SMC) phenotype. We have previously shown that abdominal aortic aneurysm progression in a mouse model of the disease is associated with reduced differentiation of SMCs within the lesion and that cyclooxygenase-2 (COX-2) is critical to initiation and progression of the aneurysms. The current studies utilized human aortic SMC (hASMC) cultures to better characterize mechanisms responsible for COX-2-dependent modulation of the SMC phenotype. Depending on the culture conditions, hASMCs expressed multiple characteristics of a differentiated and contractile phenotype, or a de-differentiated and secretory phenotype. The pharmacological inhibition of COX-2 promoted the differentiated phenotype whereas treatment with the COX-2-derived metabolite prostaglandin E2 (PGE2) increased characteristics of the de-differentiated phenotype. Furthermore, pharmacological inhibition or siRNA-mediated knockdown of microsomal prostaglandin E synthase-1 (mPGES-1), the enzyme that functions down-stream of COX-2 during the synthesis of PGE2, significantly increased expression of characteristics of the differentiated SMC phenotype. Therefore, our findings suggest that COX-2 and mPGES-1 -dependent synthesis of PGE2 contributes to a de-differentiated hASMC phenotype and that mPGES-1 may provide a novel pharmacological target for treatment of cardiovascular diseases where altered SMC differentiation has a causative role.

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Section: Resultssupporting

confidence: 53%

Section: Discussionsupporting

confidence: 56%

Microsomal Prostaglandin E Synthase-1 Expression by Aortic Smooth Muscle Cells Attenuates the Differentiated Phenotype

Adedoyin

Loftin²

2016

Journal of Cardiovascular Pharmacology

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“…The two novel mPGES1 inhibitors produced analgesia equivalent to diclofenac in a guinea pig model of knee joint pain (mono iodoacetate model of arthritis). mPGES1 inhibition therefore represents a novel approach for the management of inflammatory pain, likely without the adverse cardiovascular (myocardial infarction) and gastrointestinal bleeding adverse effects of COX2 inhibitors 239 .…”

Section: Enzymes As Analgesic Drug Targetsmentioning

confidence: 99%

Breaking barriers to novel analgesic drug development

Yekkirala

Roberson

Bean

et al. 2017

Nat Rev Drug Discov

277

246

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Acute and chronic pain complaints, while very common, are generally poorly served by existing therapies. The unmet clinical need reflects the failure in developing novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms coupled with the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities to develop new therapeutic strategies and revisit existing targets, including modulating ion channels, enzymes and GPCRs.

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“…mPGES-1 also has been shown to exacerbate epileptic seizures and hippocampal gliosis in mouse pentylenetetrazol seizure model [128]. The first clinical trial with the mPGES-1 inhibitor LY3023703 (structure not disclosed) by Eli Lilly and Company (https://clinicaltrials.gov/show/NCT01872910) reveals more potent inhibition of PGE 2 synthesis than COX-2 inhibitor celecoxib without decreasing PGI 2 levels in the blood [129]. Thus, blockade of mPGES-1 by small molecules should be explored as an anti-inflammatory therapy for epilepsy in the future [128, 130].…”

Section: Other Potential Anti-inflammatory Targets For Small Moleculesmentioning

confidence: 99%

Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

Dey

Jiang

et al. 2016

Trends in Pharmacological Sciences

170

132

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As a crucial component of brain innate immunity, neuroinflammation initially contributes to neuronal tissue repair and maintenance. However, chronic inflammatory processes within the brain and associated blood-brain barrier impairment often cause neurotoxicity and hyperexcitability. Mounting evidence points to a mutual facilitation between inflammation and epilepsy, suggesting that blocking the undesired inflammatory signaling within the brain might provide novel strategies to treat seizures and epilepsy. Neuroinflammation is primarily characterized by the upregulation of proinflammatory mediators in epileptogenic foci, among which, cyclooxygenase-2/prostaglandin E2, interleukin-1β, transforming growth factor-β, toll-like receptor 4, high-mobility group box 1, and tumor necrosis factor-α have been extensively studied. Small molecules that specifically target these key proinflammatory perpetrators have been evaluated for antiepileptic and antiepileptogenic effects in animal models. These important preclinical studies provide new insights into the regulation of inflammation in epileptic brains and guide drug discovery efforts aimed at developing novel anti-inflammatory therapies for seizures and epilepsy.

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Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandin e synthase 1 inhibitor, with celecoxib

Cited by 59 publications

References 18 publications

Microsomal Prostaglandin E Synthase-1 Expression by Aortic Smooth Muscle Cells Attenuates the Differentiated Phenotype

Microsomal Prostaglandin E Synthase-1 Expression by Aortic Smooth Muscle Cells Attenuates the Differentiated Phenotype

Breaking barriers to novel analgesic drug development

Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

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