title: Identification and Characterization of Novel Microsomal Prostaglandin E Synthase-1 Inhibitors for Analgesia.
abstract: Prostaglandin (PG) E2 plays a critical role in eliciting inflammation. Nonsteroidal anti-inflammatory drugs and selective inhibitors of cyclooxygenase, which block PGE2 production, have been used as key agents in treating inflammation and pain associated with arthritis and other conditions. However, these agents have significant side effects such as gastrointestinal bleeding and myocardial infarction, since they also block the production of prostanoids that are critical for other normal physiologic functions. Microsomal prostaglandin E2 synthase-1 is a membrane-bound terminal enzyme in the prostanoid pathway, which acts downstream of cyclooxygenase 2 and is responsible for PGE2 production during inflammation. Thus, inhibition of this enzyme would be expected to block PGE2 production without inhibiting other prostanoids and would provide analgesic efficacy without the side effects. In this report, we describe novel microsomal prostaglandin E2 synthase-1 inhibitors that are potent in blocking PGE2 production and are efficacious in a guinea pig monoiodoacetate model of arthralgia. These molecules may be useful in treating the signs and symptoms associated with arthritis.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Chandrasekhar
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Anita K
authors.initials: AK
authors.lastname: Harvey
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Xiao-Peng
authors.initials: XP
authors.lastname: Yu
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana markgchambers@lilly.com.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Chambers
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Oskins
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Chaohua
authors.initials: C
authors.lastname: Lin
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Seng
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Thibodeaux
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Bryan H
authors.initials: BH
authors.lastname: Norman
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Hughes
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Schiffler
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fisher
mesh_terms: D000698:Analgesia / Q000379:methods; D000700:Analgesics / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000068579:Celecoxib / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010616:Phenanthrenes / Q000737:chemistry* / Q000494:pharmacology*; D000071876:Prostaglandin-E Synthases; D051381:Rats
chemical_list: D000700:Analgesics; D004791:Enzyme Inhibitors; D007093:Imidazoles; C526699:MF63 compound; D010616:Phenanthrenes; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D000068579:Celecoxib