KR33426, [2-(2,5-dichlorophenyl)-5-methyloxazol-4yl]carbonylguanidine, is a novel compound to be effective on mouse systemic lupus erythematosus

• Published in: European journal of pharmacology Vol. 668; no. 3; pp. 459 - 466
• Main Authors: Lee, Geun-Hee, Oh, Jin-Mi, Kim, Hyun-Sun, Yoon, Won-Kee, Yi, Kyu Yang, Yang, Young, Han, Seung-Hyun, Lee, Sunkyung, Moon, Eun-Yi
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 15.10.2011; Elsevier
• Subjects: Animals; Apoptosis - drug effects; B cell; B-Cell Activating Factor - metabolism; B-Cell Activation Factor Receptor - metabolism; B-Lymphocytes - drug effects; B-Lymphocytes - pathology; BAFF; Biological and medical sciences; Carbonylguanidine derivative; Cell Proliferation - drug effects; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Guanidines - pharmacology; Guanidines - therapeutic use; histopathology; KR33426; lupus erythematosus; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - metabolism; lymphocyte proliferation; Medical sciences; Mice; Oxazoles - pharmacology; pharmacology; Pharmacology. Drug treatments; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; screening; Spleen - immunology; splenocytes; Systemic lupus erythematosus; therapeutics; BAFF; B cell; Systemic lupus erythematosus; KR33426; Carbonylguanidine derivative; Immunopathology; Connective tissue disease; Skin disease; Rodentia; Autoimmune disease; B-Lymphocyte; Vertebrata; Mammalia; Mouse; Animal; Systemic disease; Oxazole derivatives
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2011.07.026

B cell-activating factor (BAFF) is a key regulator of B lymphocyte development. Signals from BAFF are transmitted through binding to a specific BAFF receptor (BAFF-R). Here, we established screening method to find a specific inhibitor for the interference of BAFF–BAFF-R interactions. We screened oxazole-4-carbonylguanidine derivatives and selected KR33426, [2-(2,5-dichlorophenyl)-5-methyloxazol-4yl]carbonylguanidine, as a candidate to interfere BAFF–BAFF-R interactions. KR33426 inhibited BAFF-mediated anti-apoptotic effect on splenocytes as judged by hypodiploid cell formation. KR33426 also increased the degradation of procaspase-3 that was inhibited by BAFF protein. In addition, we examined whether KR33426 was effective on the treatment of systemic lupus erythematosus-like symptom in MRL lpr/lpr mouse. When 5 or 10 mg/kg KR33426 was intraperitoneally administered to MRL lpr/lpr mice for 4 weeks, histopathological changes were ameliorated in the narrowed space between renal glomerulus and glomerulus capsule. KR33426 reduced B220 + B cell population and B cell mitogen, lipopolysaccharide-stimulated lymphocyte proliferation in splenocytes. KR33426 attenuated an increase in CD43 −IgM + immature pro-B and a decrease in CD21 + IgM + T2-B and IgD + IgM −recirculating-B cells on B cell development. Data show that KR33426 inhibits BAFF–BAFF-R interactions and it is effective on the treatment of systemic lupus erythematosus-like symptom in MRL lpr/lpr mice. Thus, it suggests that KR33426 is a novel candidate to develop anti-autoimmune therapeutics by the interference of BAFF–BAFF-R interactions, specifically.