Discovery of Tetrahydropyrazolopyridine as Sphingosine 1-Phosphate Receptor 3 (S1P3)-Sparing S1P1 Agonists Active at Low Oral Doses

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• 作者：Emmanuel H. Demont ; James M. Bailey ; Rino A. Bit ; Jack A. Brown ; Colin A. Campbell ; Nigel Deeks ; Simon J. Dowell ; Colin Eldred ; Pam Gaskin ; James R. J. Gray ; Andrea Haynes ; David J. Hirst ; Duncan S. Holmes ; Umesh Kumar ; Mary A. Morse ; Greg J. Osborne ; Jessica F. Renaux ; Gail A. L. Seal ; Chris A. Smethurst ; Simon Taylor ; Robert Watson ; Robert Willis ; Jason Witherington
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：59
• 期：3
• 页码：1003-1020
• 全文大小：687K
• ISSN：1520-4804

文摘

FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing–remitting multiple sclerosis. It is a potent agonist of the S1P₁ receptor, but its lack of selectivity against the S1P₃ receptor has been linked to most of the cardiovascular side effects observed in the clinic. These findings have triggered intensive efforts toward the identification of a second generation of S1P₃-sparing S1P₁ agonists. We have recently disclosed a series of orally active tetrahydroisoquinoline (THIQ) compounds matching these criteria. In this paper we describe how we defined and implemented a strategy aiming at the discovery of selective structurally distinct follow-up agonists. This effort culminated with the identification of a series of orally active tetrahydropyrazolopyridines.