title: Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation.
abstract: A critical component of innate immune response to infection and tissue damage is the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome, and this pathway and its activation products have been implicated in the pathophysiology of a variety of diseases. NLRP3 inflammasome activation leads to the cleavage of pro-IL-1β and pro-IL-18, as well as the subsequent release of biologically active IL-1β, IL-18, and other soluble mediators of inflammation. In this study, we further define the pharmacology of the previously reported NLRP3 inflammasome-selective, IL-1β processing inhibitor CP-456,773 (also known as MCC950), and we demonstrate its efficacy in two in vivo models of inflammation. Specifically, we show that in human and mouse innate immune cells CP-456,773 is an inhibitor of the cellular release of IL-1β, IL-1α, and IL-18, that CP-456,773 prevents inflammasome activation induced by disease-relevant soluble and crystalline NLRP3 stimuli, and that CP-456,773 inhibits R848- and imiquimod-induced IL-1β release. In mice, CP-456,773 demonstrates potent inhibition of the release of proinflammatory cytokines following acute i.p. challenge with LPS plus ATP in a manner that is proportional to the free/unbound concentrations of the drug, thereby establishing an in vivo pharmacokinetic/pharmacodynamic model for CP-456,773. Furthermore, CP-456,773 reduces ear swelling in an imiquimod cream-induced mouse model of skin inflammation, and it reduces airway inflammation in mice following acute challenge with house dust mite extract. These data implicate the NLRP3 inflammasome in the pathogenesis of dermal and airway inflammation, and they highlight the utility of CP-456,773 for interrogating the contribution of the NLRP3 inflammasome and its outputs in preclinical models of inflammation and disease.
authors: Inflammation & Immunology Research Unit, Pfizer, Cambridge, MA 02139;
authors: Michael J
authors: MJ
authors: Primiano
authors: Department of Medicinal Chemistry, Pfizer, Cambridge, MA 02139;
authors: Bruce A
authors: 0000-0003-0859-6956
authors: BA
authors: Lefker
authors: Inflammation & Immunology Research Unit, Pfizer, Cambridge, MA 02139;
authors: Michael R
authors: 0000-0002-7801-0220
authors: MR
authors: Bowman
authors: Inflammation & Immunology Research Unit, Pfizer, Cambridge, MA 02139;
authors: Andrea G
authors: AG
authors: Bree
authors: Inflammation & Immunology Research Unit, Pfizer, Cambridge, MA 02139;
authors: Cedric
authors: 0000-0001-9869-6445
authors: C
authors: Hubeau
authors: Primary Pharmacology Group, Pfizer, Groton, CT 06340;
authors: Paul D
authors: PD
authors: Bonin
authors: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany; German Center for Neurodegenerative Diseases, 53175 Bonn, Germany;
authors: Matthew
authors: M
authors: Mangan
authors: Inflammation & Immunology Research Unit, Pfizer, Cambridge, MA 02139;
authors: Ken
authors: K
authors: Dower
authors: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 06105; and.
authors: Brian G
authors: 0000-0003-4008-3093
authors: BG
authors: Monks
authors: Inflammation & Immunology Research Unit, Pfizer, Cambridge, MA 02139;
authors: Leah
authors: L
authors: Cushing
authors: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge MA 02139.
authors: Stephen
authors: 0000-0003-3362-7507
authors: S
authors: Wang
authors: Inflammation & Immunology Research Unit, Pfizer, Cambridge, MA 02139;
authors: Julia
authors: J
authors: Guzova
authors: Inflammation & Immunology Research Unit, Pfizer, Cambridge, MA 02139;
authors: Aiping
authors: 0000-0002-9797-1924
authors: A
authors: Jiao
authors: Inflammation & Immunology Research Unit, Pfizer, Cambridge, MA 02139;
authors: Lih-Ling
authors: LL
authors: Lin
authors: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany; German Center for Neurodegenerative Diseases, 53175 Bonn, Germany; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 06105; and.
authors: Eicke
authors: E
authors: Latz
authors: Department of Medicinal Chemistry, Pfizer, Cambridge, MA 02139;
authors: David
authors: D
authors: Hepworth
authors: Inflammation & Immunology Research Unit, Pfizer, Cambridge, MA 02139; james.p.hall@pfizer.com.
authors: J Perry
authors: JP
authors: Hall
mesh_terms: D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000276:immunology; D003872:Dermatitis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D005663:Furans; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007192:Indenes; D058847:Inflammasomes / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors*; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D015398:Signal Transduction; D013449:Sulfonamides; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D005663:Furans; D006576:Heterocyclic Compounds, 4 or More Rings; D007192:Indenes; D058847:Inflammasomes; D020382:Interleukin-18; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D013449:Sulfonamides; D013450:Sulfones; C000597426:N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide