title: Multitargeting of selected prostanoid receptors provides agents with enhanced anti-inflammatory activity in macrophages.
abstract: A polypharmacologic approach to prostanoid based anti-inflammatory therapeutics was undertaken in order to exploit both the anti- and proinflammatory properties attributed to the various prostanoid receptors. Multitargeting of selected prostanoid receptors yielded a prototype compound, compound 1 (AGN 211377), that antagonizes prostaglandin D2 receptors (DPs) DP1 (49) and DP2 (558), prostaglandin E2 receptors (EPs) EP1 (266) and EP4 (117), prostaglandin F2α receptor (FP) (61), and thromboxane A2 receptor (TP) (11) while sparing EP2, EP3, and prostaglandin I2 receptors (IPs); Kb values (in nanomoles) are given in parentheses. Compound 1 evoked a pronounced inhibition of cytokine/chemokine secretion from lipopolysaccharide or TNF-α stimulated primary human macrophages. These cytokine/chemokines included cluster of designation 40 receptor (CD40), epithelial-derived neutrophil-activating protein 78 (ENA-78), granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), IL-8, IL-18, monocyte chemotactic protein-1 (CCL2) (MCP-1), tissue plasminogen activator inhibitor (PAI-1), and regulated on activation, normal T cell expressed and secreted (RANTES). In contrast, the inhibitory effects of most antagonists selective for a single receptor were modest or absent, and selective EP2 receptor blockade increased cytokine release in some instances. Compound 1 also showed clear superiority to the cyclooxygenase inhibitors diclofenac and rofecoxib. These findings reveal that blockade of multiple prostanoid receptors, with absent antagonism of EP2 and IP, may provide more effective anti-inflammatory activity than global suppression of prostanoid synthesis or highly selective prostanoid receptor blockade. These investigations demonstrate the first working example of prostanoid receptor polypharmacology for potentially safer and more effective anti-inflammatory therapeutics by blocking multiple proinflammatory receptors while sparing those with anti-inflammatory activity.
authors.affiliation: *Department of Biological Sciences, Allergan, Incorporated, Irvine, California, USA; Department of Bioengineering, Imperial College London, London, United Kingdom; Drug Discovery Department, Selcia Limited, Ongar, United Kingdom; and Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Jenny W
authors.initials: JW
authors.lastname: Wang
authors.affiliation: *Department of Biological Sciences, Allergan, Incorporated, Irvine, California, USA; Department of Bioengineering, Imperial College London, London, United Kingdom; Drug Discovery Department, Selcia Limited, Ongar, United Kingdom; and Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA david.woodward@imperial.ac.uk.
authors.forename: David F
authors.initials: DF
authors.lastname: Woodward
authors.affiliation: *Department of Biological Sciences, Allergan, Incorporated, Irvine, California, USA; Department of Bioengineering, Imperial College London, London, United Kingdom; Drug Discovery Department, Selcia Limited, Ongar, United Kingdom; and Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Martos
authors.affiliation: *Department of Biological Sciences, Allergan, Incorporated, Irvine, California, USA; Department of Bioengineering, Imperial College London, London, United Kingdom; Drug Discovery Department, Selcia Limited, Ongar, United Kingdom; and Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Clive L
authors.initials: CL
authors.lastname: Cornell
authors.affiliation: *Department of Biological Sciences, Allergan, Incorporated, Irvine, California, USA; Department of Bioengineering, Imperial College London, London, United Kingdom; Drug Discovery Department, Selcia Limited, Ongar, United Kingdom; and Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Carling
authors.affiliation: *Department of Biological Sciences, Allergan, Incorporated, Irvine, California, USA; Department of Bioengineering, Imperial College London, London, United Kingdom; Drug Discovery Department, Selcia Limited, Ongar, United Kingdom; and Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kingsley
authors.affiliation: *Department of Biological Sciences, Allergan, Incorporated, Irvine, California, USA; Department of Bioengineering, Imperial College London, London, United Kingdom; Drug Discovery Department, Selcia Limited, Ongar, United Kingdom; and Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D002478:Cells, Cultured; D002934:Cinnamates / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity
chemical_list: C000608115:AGN 211377; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002934:Cinnamates; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane
keywords: NSAID; inflammation; polypharmacology; receptor antagonism