Novel S1P1 Receptor Agonists 鈥?Part 1: From Pyrazoles to Thiophenes

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• 作者：Martin H. Bolli ; Claus M眉ller ; Boris Mathys ; Stefan Abele ; Magdalena Birker ; Roberto Bravo ; Daniel Bur ; Patrick Hess ; Christopher Kohl ; David Lehmann ; Oliver Nayler ; Markus Rey ; Solange Meyer ; Michael Scherz ; Gunther Schmidt ; Beat Steiner ; Alexander Treiber ; J枚rg Velker ; Thomas Weller
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9737-9755
• 全文大小：680K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

From a high-throughput screening campaign aiming at the identification of novel S1P₁ receptor agonists, the pyrazole derivative 2 emerged as a hit structure. Medicinal chemistry efforts focused not only on improving the potency of the compound but in particular also on resolving its inherent instability issue. This led to the discovery of novel bicyclo[3.1.0]hexane fused thiophene derivatives. Compounds with high affinity and selectivity for S1P₁ efficiently reducing the blood lymphocyte count in the rat were identified. For instance, compound 85 showed EC₅₀ values of 7 and 2880 nM on S1P₁ and S1P₃, respectively, had favorable pharmacokinetic properties in rat and dog, distributed well into brain tissue, and efficiently and dose dependently reduced the blood lymphocyte count in the rat. After oral administration to spontaneously hypertensive rats, the S1P₁ selective compound 85 showed no effect on mean arterial blood pressure and affected the heart rate during the wake phase of the animals only.