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

• Published in: Bioorganic & medicinal chemistry letters 2004-08, Vol.14 (16), p.4307-4311
• Main Authors: Weidner-Wells, Michele A, Henninger, Todd C, Fraga-Spano, Stephanie A, Boggs, Christine M, Matheis, Michele, Ritchie, David M, Argentieri, Dennis C, Wachter, Michael P, Hlasta, Dennis J
• Format: Article
• Language: English
• Subjects: Administration, Oral; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Diarylisoxazoles; IL-8; Inflammation; Isoxazoles - administration & dosage; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - pharmacology; Medical sciences; Oxadiazoles - administration & dosage; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Pharmacology. Drug treatments; Receptors, Interleukin-8A - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.05.080

A novel series of 3,5-diarylisoxazole and 3,5-diaryl-1,2,4-oxadiazole IL-8 antagonists has been identified. These compounds also are active in a functional elastase assay. One of the compounds exhibits oral activity in a rat adjuvant arthritis model. A novel series of 3,5-diarylisoxazole and 3,5-diaryl-1,2,4-oxadiazole IL-8 inhibitors has been identified. These compounds exhibit activity in an IL-8 binding assay as well as in a functional assay of IL-8 induced elastase release from neutrophils. In addition, one of the compounds exhibits oral activity in a rat adjuvant arthritis model.