Optimization of a Potent, Orally Active S1P1 Agonist Containing a Quinolinone Core

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• 作者：Paul E. Harrington ; Michael D. Croghan ; Christopher Fotsch ; Mike Frohn ; Brian A. Lanman ; Lewis D. Pennington ; Alexander J. Pickrell ; Anthony B. Reed ; Kelvin K. C. Sham ; Andrew Tasker ; Heather A. Arnett ; Michael Fiorino ; Matthew R. Lee ; Michele McElvain ; Henry G. Morrison ; Han Xu ; Yang Xu ; Xuxia Zhang ; Min Wong ; Victor J. Cee
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：January 12, 2012
• 年：2012
• 卷：3
• 期：1
• 页码：74-78
• 全文大小：277K
• 年卷期：v.3,no.1(January 12, 2012)
• ISSN：1948-5875

文摘

The optimization of a series of S1P₁ agonists with limited activity against S1P₃ is reported. A polar headgroup was used to improve the physicochemical and pharmacokinetic parameters of lead quinolinone 6. When dosed orally at 1 and 3 mg/kg, the azahydroxymethyl analogue 22 achieved statistically significant lowering of circulating blood lymphocytes 24 h postdose. In rats, a dose-proportional increase in exposure was measured when 22 was dosed orally at 2 and 100 mg/kg.

Keywords:

Sphingosine-1-phosphate receptor; S1P₁; agonist; multiple sclerosis