Discovery of AMG 369, a Thiazolo[5,4-b]pyridine Agonist of S1P1 and S1P5
Discovery of AMG 369, a Thiazolo[5,4-b]pyridine Agonist of S1P1 and S1P5
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DOI：
10.1021/ml100306h
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发表时间：
2011-02-01
影响因子：
4.2
通讯作者：
Buerli, Roland W.
中科院分区：
文献类型：
--
作者：
Cee, Victor J.;Frohn, Mike;Buerli, Roland W.
报道了一系列对 S1P(3) 受体活性有限的噻唑并吡啶 S1P(1) 激动剂的优化。这些努力发现了 1-(3-氟-4-(5-(1-苯基环丙烯)噻唑并[5,4-b]吡啶-2基)苯甲基)-氮杂环丁烷-3-羧酸 (5d, AMG 369)，这是一种有效的双重 S1P(1)/S1P(5) 激动剂，在 S1P(3) 上活性有限，在 S1P(3) 上没有活性。 S1P(2)/S1P(4)。以 0.1 mg/kg 口服给药 5 天，可减少给药后 24 小时的血液淋巴细胞计数，延迟大鼠实验性自身免疫性脑脊髓炎的发病并减轻其严重程度。
The optimization of a series of thiazolopyridine S1P(1) agonists with limited activity, at the S1P(3) receptor is reported. These efforts resulted in the discovery of 1-(3-fluoro-4-(5-(1-phenylcycloprol)thiazolo[5,4-b]pyridin-2yl)benzyl)-azetidine-3-carboxylic acid (5d, AMG 369), a potent dual S1P(1)/S1P(5) agonist with limited activity at S1P(3) and no activity at S1P(2)/S1P(4). Dosed orally at 0.1 mg/kg, 5d is shown to reduce blood lymphocyte counts 24 h postdose and delay the onset and reduce the severity of experimental autoimmune encephalomyelitis in rat.