title: Development of orally bioavailable bicyclic pyrazolones as inhibitors of tumor necrosis factor-alpha production.
abstract: 2-Aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel bicyclic pyrazolone core, are described. Many showed low-nanomolar activity against lipopolysaccharide-induced TNF-alpha production in monocytic cells. Secondary screening data are presented for the pyrimidinyl bicyclic pyrazolones. Several of these analogues showed good oral bioavailability in rat and efficacy in the rat iodoacetate in vivo model.
authors.affiliation: Health Care Research Center, Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA. clark.mp@pg.com
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clark
authors.forename: Steven K
authors.initials: SK
authors.lastname: Laughlin
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Laufersweiler
authors.forename: Roger G
authors.initials: RG
authors.lastname: Bookland
authors.forename: Todd A
authors.initials: TA
authors.lastname: Brugel
authors.forename: Adam
authors.initials: A
authors.lastname: Golebiowski
authors.forename: Mark P
authors.initials: MP
authors.lastname: Sabat
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Townes
authors.forename: John C
authors.initials: JC
authors.lastname: VanRens
authors.forename: Jane F
authors.initials: JF
authors.lastname: Djung
authors.forename: Michael G
authors.initials: MG
authors.lastname: Natchus
authors.forename: Biswanath
authors.initials: B
authors.lastname: De
authors.forename: Lily C
authors.initials: LC
authors.lastname: Hsieh
authors.forename: Susan C
authors.initials: SC
authors.lastname: Xu
authors.forename: Rick L
authors.initials: RL
authors.lastname: Walter
authors.forename: Marlene J
authors.initials: MJ
authors.lastname: Mekel
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Heitmeyer
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Brown
authors.forename: Karen
authors.initials: K
authors.lastname: Juergens
authors.forename: Yetunde O
authors.initials: YO
authors.lastname: Taiwo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Janusz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006801:Humans; D066298:In Vitro Techniques; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D010770:Phosphotransferases