Prostanoid Receptor Antagonist Effects on Intraocular Pressure, Supported by Ocular Biodisposition Experiments

Woodward, David F.; Wenthur, Stacey; Rudebush, Tara; Fan, Shan; Toris, Carol B.

doi:10.1089/jop.2016.0069

Cited by 9 publications

(6 citation statements)

References 51 publications

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“…The pharmacokinetic methods were previously and extensively described. 31 The pharmacokinetic studies presented herein were performed at Medicilon Preclinical Research (Shanghai) LLC (Shanghai, China). Male New Zealand white rabbits, weighing 1.79 to 2.95 kg, were used in the study.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

A Second Generation Prostanoid Receptor Antagonist Acting at Multiple Receptor Subtypes

Woodward

Wang

Spada

et al. 2020

ACS Pharmacol. Transl. Sci.

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It has previously been reported that a prototypical compound (AGN 211377), which blocks pro-inflammatory prostanoid receptors (DP 1 , DP 2 , EP 1 , EP 4, FP, TP) and leaves open IP and EP 2 receptors so that their anti-inflammatory properties could be exerted, produced superior inhibitory effects on cytokine release from human macrophages compared to cyclooxygenase (COX) inhibitors. This favorable activity profile translated into animal studies, with AGN 211377 exceeding the level of inhibition afforded by COX inhibition. AGN 211377 was not, however, a practical drug candidate, having poor bioavailability and cost of goods concerns. Compound 1 (designated AGN 225660) represents a second-generation compound with an entirely different "druggable" core structure. Such a dramatic change in chemical scaffold created uncertainty with respect to matching the effects of AGN 211377. AGN 225660 inhibited RANTES, IL-8, and MCP-1 secretion by at least 50%, from TNFα activated human macrophages. Although AGN 225660 reduced TNFα-evoked MCP-1 release from human monocyte-derived macrophages, it increased LPS-induced MCP-1 secretion (up to 2-fold) from human monocyte-derived dendritic cells. However, AGN 225660 inhibited the release of IL12p 70 and IL-23 from human monocyte-derived dendritic cells stimulated by LPS by more than 70%. This effect of AGN 225660 was reproduced in part by the prototype compound AGN 211377 and a combination of selective DP 1 , EP 1 , EP 4 , FP, and TP antagonists. These findings suggest important effects on T cell skewing and disease modification by this class of therapeutic agents. AGN 225660 exhibited good ocular bioavailability and was active in reducing ocular inflammation associated with phacoemulsification surgery, LPS, and arachidonic acid induced uveitis.

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Section: ■ Results and Discussionmentioning

confidence: 99%

A Second Generation Prostanoid Receptor Antagonist Acting at Multiple Receptor Subtypes

Woodward

Wang

Spada

et al. 2020

ACS Pharmacol. Transl. Sci.

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“…Membranes were prepared from 1321 NI astrocytoma cells (Sigma‐Aldrich, Gillingham, Dorset, UK)) stably expressing human recombinant DP 1 receptors (Woodward et al, , Wang et al, ). For assays, membranes (protein 15 μg per well) expressing the human DP 1 receptor were incubated in Millipore Multiscreen HTS ‐HV (0.45 μm) plates containing assay buffer (50 mM Tris, 5 mM MgCl 2 , 10 μg·mL −1 saponin and 10 mM indomethacin), [ 3 H] PGD 2 3.2 nM and the test compounds (0.1 to 10 000 nM) at pH 7.4.…”

Section: Methodsmentioning

confidence: 99%

The affinity, intrinsic activity and selectivity of a structurally novel EP₂ receptor agonist at human prostanoid receptors

Coleman¹,

Woodrooffe²,

Clark³

et al. 2019

British J Pharmacology

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Background and PurposeProstanoid EP2 receptor agonists exhibit several activities including ocular hypotension, tocolysis and anti‐inflammatory activity. This report describes the affinity and selectivity of a structurally novel, non‐prostanoid EP2 receptor agonist, PGN‐9856, and its therapeutic potential.Experimental ApproachThe pharmacology of a series of non‐prostanoid EP2 receptor agonists was determined according to functional and radioligand binding studies, mostly using human recombinant prostanoid receptor transfectants. The selectivity of PGN‐9856, as the preferred compound, was subsequently determined by using a diverse variety of non‐prostanoid target proteins. The therapeutic potential of PGN‐9856 was addressed by determining its activity in relevant primate cell, tissue and disease models.Key ResultsPGN‐9856 was a selective and high affinity (pKi ≥ 8.3) ligand at human recombinant EP2 receptors. In addition to high affinity binding, it was a potent and full EP2 receptor agonist with a high level of selectivity at EP1, EP3, EP4, DP, FP, IP and TP receptors. In cells overexpressing human recombinant EP2 receptors, PGN‐9856 displayed a potency (pEC50≥ 8.5) and a maximal response (increase in cAMP) comparable to that of the endogenous agonist PGE2. PGN‐9856 exhibited no appreciable affinity (up 10 μM) for a range of 53 other receptors, ion channels and enzymes. Finally, PGN‐9856 exhibited tocolytic, anti‐inflammatory and long‐acting ocular hypotensive properties consistent with its potent EP2 receptor agonist properties.Conclusions and ImplicationsPGN‐9856 is a potent, selective and efficacious prostanoid EP2 receptor agonist with diverse potential therapeutic applications: tocolytic, anti‐inflammatory and notably anti‐glaucoma.

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“…The periorbital delivery method may mitigate adverse effects and present a pharmacologic advantage. It has been shown that bimatoprost tends to accumulate in the eyelids and palpebral conjunctiva 54,55 . As the palpebral conjunctiva overlies the limbus and sclera, and scleral penetration of prostanoid drugs is comparatively higher than via the cornea, application of very potent drugs like EP2 agonists via the periocular tissue may provide a slow‐release drug depot, presuming that this tissue will more slowly hydrolyze the ester 53 .…”

Section: Prostaglandin Devicesmentioning

confidence: 99%

Medical anti‐glaucoma therapy: Beyond the drop

Miller

Eaton

2020

Veterinary Ophthalmology

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Barriers to effective medical therapy are numerous and include difficulties with effective and sustained control of intraocular pressure (IOP) and adherence to prescribed anti‐glaucoma drop regimens. In an effort to circumvent these challenges, a number of new anti‐glaucoma therapies with sustained effects have emerged. Methods for sustained delivery of prostaglandin analogs are being intensely investigated and many are in human clinical trials. Intracameral devices include the following: Allergan's Durysta™ Bimatoprost SR, Envisia Therapeutics’ ENV515 travoprost implant, Glaukos’ iDose™, Ocular Therapeutix's OTX‐TIC travoprost implant, and Santen's polycaprolactone implant with PGE2‐derivative DE‐117. Other prostaglandin‐based technologies include Allergan's bimatoprost ring (placed in the conjunctival fornix), Ocular Therapeutics’ OTX‐TP intracanalicular travoprost implant, subconjunctival latanoprost in a liposomal formulation, and the PGE2 derivative PGN 9856‐isopropyl ester that is applied to the periorbital skin. Exciting breakthroughs in gene therapy include using viral vectors to correct defective genes such as MYOC or to modulate gonioimplant fibrosis, CRISPR technology to edit MYOC or to alter aquaporin to reduce aqueous humor production, and siRNA technology to silence specific genes. Stem cell technology can repopulate depleted tissues or, in the case of Neurotech's Renexus® NT‐501 intravitreal implant, serve as a living drug delivery device that continuously secretes neurotrophic factors. Other unique approaches involve nanotechnology, nasal sprays that deliver drug directly to the optic nerve and noninvasive alternating current stimulation of surviving cells in the optic nerve. Over time these modalities are likely to challenge the preeminent role that drops currently play in the medical treatment of glaucoma in animals.

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Prostanoid Receptor Antagonist Effects on Intraocular Pressure, Supported by Ocular Biodisposition Experiments

Cited by 9 publications

References 51 publications

A Second Generation Prostanoid Receptor Antagonist Acting at Multiple Receptor Subtypes

A Second Generation Prostanoid Receptor Antagonist Acting at Multiple Receptor Subtypes

The affinity, intrinsic activity and selectivity of a structurally novel EP₂ receptor agonist at human prostanoid receptors

Medical anti‐glaucoma therapy: Beyond the drop

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Prostanoid Receptor Antagonist Effects on Intraocular Pressure, Supported by Ocular Biodisposition Experiments

Cited by 9 publications

References 51 publications

A Second Generation Prostanoid Receptor Antagonist Acting at Multiple Receptor Subtypes

A Second Generation Prostanoid Receptor Antagonist Acting at Multiple Receptor Subtypes

The affinity, intrinsic activity and selectivity of a structurally novel EP2 receptor agonist at human prostanoid receptors

Medical anti‐glaucoma therapy: Beyond the drop

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Product

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The affinity, intrinsic activity and selectivity of a structurally novel EP₂ receptor agonist at human prostanoid receptors