title: Benzenesulfonamide indole inhibitors of cytosolic phospholipase A2alpha: optimization of in vitro potency and rat pharmacokinetics for oral efficacy.
abstract: The synthesis and structure-activity relationship of a series of benzenesulfonamide indole inhibitors of cPLA(2)alpha are described. Substitution of the benzenesulfonamide led to analogues with 50-fold improvement in potency versus the unsubstituted benzenesulfonamide lead compound. Rat pharmacokinetics in a minimal formulation was used to prioritize compounds, leading to the discovery of a potent inhibitor of cPLA(2)alpha with oral efficacy in models of rat carrageenan paw edema and Ascaris suum airway challenge in naturally sensitized sheep.
authors.affiliation: Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. klee@wyeth.com
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Lee
authors.forename: Mark L
authors.initials: ML
authors.lastname: Behnke
authors.forename: Megan A
authors.initials: MA
authors.lastname: Foley
authors.forename: Lihren
authors.initials: L
authors.lastname: Chen
authors.forename: Weiheng
authors.initials: W
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: Vargas
authors.forename: Jill
authors.initials: J
authors.lastname: Nunez
authors.forename: Steve
authors.initials: S
authors.lastname: Tam
authors.forename: Nevena
authors.initials: N
authors.lastname: Mollova
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Marina W H
authors.initials: MW
authors.lastname: Shen
authors.forename: Manjunath K
authors.initials: MK
authors.lastname: Ramarao
authors.forename: Debra G
authors.initials: DG
authors.lastname: Goodwin
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Nickerson-Nutter
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
authors.forename: Cara
authors.initials: C
authors.lastname: Williams
authors.forename: James D
authors.initials: JD
authors.lastname: Clark
authors.forename: John C
authors.initials: JC
authors.lastname: McKew
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001196:Ascariasis / Q000188:drug therapy / Q000469:parasitology; D017165:Ascaris suum / Q000502:physiology; D002151:Calorimetry; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015394:Molecular Structure; D051381:Rats; D012756:Sheep; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D013696:Temperature; D000096926:Benzenesulfonamides
chemical_list: D054513:Group IV Phospholipases A2; D007211:Indoles; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C030374:indole