Discovery of a Novel Class of Potent and Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists
Discovery of a Novel Class of Potent and Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists
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DOI：
10.1021/jm201533b
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发表时间：
2012-02-09
影响因子：
7.3
通讯作者：
Shankar, Geetha
中科院分区：
文献类型：
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作者：
Ibrahim, Mohamed A.;Johnson, Henry W. B.;Shankar, Geetha
公开了一系列亚型选择性鞘氨醇1-磷酸受体1(S1P(1))拮抗剂。我们的高通量筛选活动揭示了命中 1，通过对化学支架进行微小修改，可以提高效力和小鼠口服暴露量。体内功效表明，高剂量的化合物12和15可抑制肿瘤生长。我们的先导系列的进一步优化导致了脯氨酸衍生物 37 (XL541) 和 38 的发现，它们在显着较低的剂量下与我们的第一代类似物具有相似的功效。类似物 37 在多个物种中表现出优异的药代动力学和口服暴露。
A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.