Metabolism of 4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (SM-8849), a novel immunomodulatory agent, in rats was investigated. By co-chromatography with authentic samples, desmethylated (SM-8800) p-hydroxylated (SL-5512) and desmethylated-p-hydroxylated SM-8849 (SL-5515) were detected in the bile. Thermospray mass spectrometry (TSP-MS) analysis of five metabolites isolated from the bile revealed molecular ions of both conjugates (glucuronides and a sulfate) and their aglycones. Aglycone structures were determined by comparison of their product spectra with those of authentic standards. Further analyses of conjugation sites were carried out by 1H-NMR including differential NOE. As a result, the sulfate of SL-5515 (5515-S), the N-glucuronides of SL-5512 and SM-8849 (5512-NG and 8849-NG, respectively), the glucuronide of SL-5512 (5512-G) and the O-glucuronide of 4-hydroxy-3-methoxy-SM-8849 (CatOMe-OG) were identified. In addition, N-methylthiouras was identified in urine by LC/MS/MS.

1996-01-01·Pharmacology4区 · 医学

The Effect of SM-8849 on Experimental Arthritis in Mice

4区 · 医学

Article

作者: Kuwabara, Kenji ; Takaoka, Yuko ; Kamada, Hiroyuki ; Kitagaki, Kunihiko ; Nagai, Hiroichi

The effect of a novel thiazole derivative, SM-8849, on experimental arthritis in mice was studied and compared to that of prednisolone. SM-8849 and prednisolone reduced the incidence and severity of type II collagen-induced arthritis in mice, as assayed by clinical observation and histopathological studies. Although both agents inhibited type II collagen-induced delayed type hypersensitivity (DTH) in arthritic mice, SM-8849 did not affect the production of humoral antibodies to type II collagen. To examine the inhibitory mechanism of SM-8849, the effects on T cell-dependent allergic inflammation were studied. SM-8849 clearly inhibited T cell-dependent reactions including staphylococcal enterotoxin B (SEB)-induced arthritis, SEB-induced CD25 expression on T cells and sheep red blood cell (SRBC)-induced DTH reaction. SM-8849, however, had no effect on the production of humoral antibody forming cells in the spleen of mice immunized with SRBC. These results indicate that inhibition of type II collagen-induced arthritis by SM-8849 is mainly due to the inactivation of T cells that are related to DTH reaction.

1994-02-01·International Journal of Immunopharmacology

Protective effects of D-penicillamine and a thiazole derivative, SM-8849, on pristane-induced arthritis in mice

Article

作者: Nishikaku, Fumio ; Koga, Yoshihiko ; Aono, Syunji

To evaluate the antiarthritic properties of a novel thiazole derivative, the drugs SM-8849, D-penicillamine and indomethacin were administered to pristane-injected DBA/1 mice. The mice were treated daily with the agents for 32 weeks, starting from the day of the pristane injection. Treatment with SM-8849 (50 mg/kg) resulted in an amelioration of arthritic disease, as assessed by clinical, radiographic, and histologic examinations. Similar results were obtained in mice treated with 50 mg/kg D-penicillamine, although this disease modifying antirheumatic drug was slightly less effective than the same dose of SM-8849. In contrast, indomethacin at the maximum tolerated dose of 2 mg/kg did not alter the course of the disease. SM-8849 and D-penicillamine were also shown to reduce serum levels of rheumatoid factors and the acute-phase reactant, serum amyloid P component. Indomethacin failed to affect either parameter. Flow cytometric analysis revealed an elevation in the T-cell population that expressed CD44, a marker of murine memory T-cells, in spleens from pristane-injected mice. SM-8849, but not D-penicillamine, prevented the increase in this cell population. These results led us to conclude that pristine-induced arthritis was a useful model for the evaluation of antirheumatic agents, in that using this model, we were able to distinguish disease modifying antirheumatic drugs from nonsteroidal anti-inflammatory drugs. Our findings also indicate that SM-8849 shows antiarthritic activity, with a unique mechanism of action, differing from that of D-penicillamine.

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适应症	最高研发状态	国家/地区	公司	日期
大便失禁	临床2期	意大利	诺金有限公司	2012-02-01
大便失禁	临床2期	匈牙利	诺金有限公司	2012-02-01
大便失禁	临床2期	瑞典	诺金有限公司	2012-02-01
大便失禁	临床2期	波兰	诺金有限公司	2012-02-01
大便失禁	临床2期	英国	诺金有限公司	2012-02-01
大便失禁	临床2期	捷克	诺金有限公司	2012-02-01
大便失禁	临床2期	法国	诺金有限公司	2012-02-01
大便失禁	临床2期	德国	诺金有限公司	2012-02-01
类风湿关节炎	临床2期	日本	Sumitomo Pharmaceuticals Co., Ltd.	-
类风湿关节炎	临床2期	-	Sumitomo Pharma Co., Ltd.	-