Discovery of a novel class of potent and orally bioavailable sphingosine 1-phosphate receptor 1 antagonists

…, GL Lewis, X Shi, RT Noguchi, M Williams…

文献索引：Ibrahim, Mohamed A.; Johnson, Henry W. B.; Jeong, Joon Won; Lewis, Gary L.; Shi, Xian; Noguchi, Robin T.; Williams, Matthew; Leahy, James W.; Nuss, John M.; Woolfrey, John; Banica, Monica; Bentzien, Frauke; Chou, Yu-Chien; Gibson, Anna; Heald, Nathan; Lamb, Peter; Mattheakis, Larry; Matthews, David; Shipway, Aaron; Wu, Xiang; Zhang, Wentao; Zhou, Sihong; Shankar, Geetha Journal of Medicinal Chemistry, 2012 , vol. 55, # 3 p. 1368 - 1381

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被引用次数: 13

摘要

A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P1) 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 ...