title: In vivo studies validating multitargeting of prostanoid receptors for achieving superior anti-inflammatory effects.
abstract: The purpose of these studies was to test the hypothesis that a selected polypharmacological approach for treating the prostanoid-mediated component of inflammatory diseases would produce a therapeutic effect superior to global inhibition of prostaglandin (PG) biosynthesis by aspirin-like drugs. The compound studied was AGN 211377, which had been previously shown to produce a superior effect on cytokine release from human macrophages compared with cyclooxygenase (COX) inhibitors. AGN 211377 antagonizes prostanoid prostaglandin D2(DP)1, DP2, prostaglandin E2(EP)1, EP4, prostaglandin F2α, and thromboxane A2receptors but not anti-inflammatory EP2, prostaglandin I2, or EP3receptors. Established rodent models of ocular inflammatory diseases were used to determine therapeutic effects in living animals. The drugs were administered systemically after predetermination of their blood levels to ensure bioavailability at an appropriate dose level. Whereas compounds selective for a single prostanoid receptor typically exhibited modest but statistically significant inhibition, AGN 211377 profoundly inhibited S-antigen-induced uveitis and laser-induced retinal neovascularization. Consistent with previous polypharmacological studies on chemokine/cytokine release from human macrophages, the prostanoid EP1receptor played a permissive role in suppressing neovascularization and inflammation in vivo Comparing AGN 211377 with a close structural congener lacking EP1antagonism (AGN 197727), AGN 197727 was much less active than AGN 211377, but pronounced anti-inflammatory and angiostatic effects were achieved by adding the EP1antagonist compound (SC-51322) to AGN 197727 in the systemic dosing regimen. Further, AGN 211377 produced superior anti-inflammatory activity compared with the nonsteroidal anti-inflammatory agent ketorolac. These results indicate the value of using a polypharmacological approach in the design of novel therapeutic agents in preference to compounds targeting a single receptor or enzyme. A compound such as AGN 211377 may represent more effective therapy than COX inhibitors in treating uveitis and ocular diseases where neovascularization is a significant part of the pathology.-Woodward, D. F., Wang, J. W., Ni, M., Bauer, A., Martos, J. L., Carling, R. W., Poloso, N. J. In vivo studies validating multitargeting of prostanoid receptors for achieving superior anti-inflammatory effects.
authors: Department of Biological Sciences, Allergan, Public Limited Company, Irvine, California, USA; and.
authors: David F
authors: DF
authors: Woodward
authors: Department of Biological Sciences, Allergan, Public Limited Company, Irvine, California, USA; and.
authors: Jenny W
authors: JW
authors: Wang
authors: Department of Biological Sciences, Allergan, Public Limited Company, Irvine, California, USA; and.
authors: Ming
authors: M
authors: Ni
authors: Department of Biological Sciences, Allergan, Public Limited Company, Irvine, California, USA; and.
authors: Alex
authors: A
authors: Bauer
authors: Discovery Department, Selcia Limited, Fyfield, United Kingdom.
authors: Jose L
authors: JL
authors: Martos
authors: Discovery Department, Selcia Limited, Fyfield, United Kingdom.
authors: Robert W
authors: RW
authors: Carling
authors: Department of Biological Sciences, Allergan, Public Limited Company, Irvine, California, USA; and poloso_neil@allergan.com.
authors: Neil J
authors: NJ
authors: Poloso
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001327:Autoimmune Diseases; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D020013:Calcium Signaling; D002934:Cinnamates / Q000494:pharmacology*; D007834:Lasers / Q000009:adverse effects; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D051381:Rats; D011917:Rats, Inbred Lew; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D012160:Retina / Q000473:pathology / Q000528:radiation effects; D012171:Retinal Vessels / Q000473:pathology / Q000528:radiation effects; D014605:Uveitis / Q000188:drug therapy / Q000209:etiology
chemical_list: C000608115:AGN 211377; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002934:Cinnamates; D011982:Receptors, Prostaglandin
keywords: antagonist; neovascularization; polypharmacology; retina; uveitis