Synthesis and structure-activity relationships of 3,5-diarylisoxazoles and 3,5-diaryl-1,2,4-oxadiazoles, novel classes of small molecule interleukin-8 (IL-8) receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 16, 2004, Pages 4307-4311

  Weidner Wells, Michele A ^a   Henninger, Todd C ^a   Fraga Spano, Stephanie A ^a   Boggs, Christine M ^a   Matheis, Michele ^a   Ritchie, David M ^a   Argentieri, Dennis C ^a   Wachter, Michael P ^a   Hlasta, Dennis J ^a  

^a JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

Diarylisoxazoles; IL 8; Inflammation

Indexed keywords

ELASTASE; INTERLEUKIN 8; INTERLEUKIN RECEPTOR; ISOXAZOLE DERIVATIVE; RECEPTOR BLOCKING AGENT;

ANTIINFLAMMATORY ACTIVITY; ARTHRITIS; ARTICLE; BINDING ASSAY; NEUTROPHIL; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ISOXAZOLES; OXADIAZOLES; RECEPTORS, INTERLEUKIN-8A; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 3142717401     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.05.080     Document Type: Article

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13. 50 of approximately 1 nM
14. Elastase assay: Neutrophils are purified from human blood by dextran sedimentation. The procedure is conducted by adding 100 μL IL-8 and 47 μL PBS to each well of a 96-well plate, followed by the addition of 3 μL drug (2.5 mM in 25% methanol) or vehicle. Neutrophils stimulated with cytochalasin B (30 μg/mL in 3% DMSO) are then added and the plate is incubated for 30 min at 37°C. The plate is then centrifuged and a fraction of the supernatant is transferred to a 96-well black plate to which 50 μL elastase substrate is added. The fluorescence of the wells is read at 0 time and at 90 min to determine the change over time (velocity) in a spectrofluorometer with an excitation @ 360 and emission @ 460. Velocity of the reaction is proportional to the amount of elastase released by IL-8 challenge since the substrate is in molar excess. Inhibition of the reaction by drug treatment is determined by comparing the drug treated wells with those treated with vehicle
15. Adjuvant-induced Arthritis model: Male Lewis rats are injected in the footpad with 0.1 mL of Mycobacteria butyricum suspended in light mineral oil at a concentration of 7.5 mg/mL. Adjuvant-induced arthritis is allowed to develop and on day 10 a baseline paw size reading is made on the uninjected paw with a mercury displacement edema computer. Dosing with test compound begins on day 10 and continues through day 14, with the paws again dipped on day 14 to measure paw swelling. Compound is administered by oral gavage and the effects of test compounds are determined by comparing the paw swelling in drug treated animals with that of vehicle treated controls