Discovery of AMG 369, a Thiazolo[5,4-b]pyridine Agonist of S1P(1) and S1P(5)

[摘要]：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)-a zetidine-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.

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