Potent and Orally Bioavailable 8-Bicyclo[2.2.2]octylxanthines as Adenosine A1 Receptor Antagonists

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• 作者：William F. Kiesman ; Jin Zhao ; Patrick R. Conlon ; James E. Dowling ; Russell C. Petter ; Frank Lutterodt ; Xiaowei Jin ; Glenn Smits ; Mary Fure ; Andrew Jayaraj ; John Kim ; Gail Sullivan ; Joel Linden
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：November 30, 2006
• 年：2006
• 卷：49
• 期：24
• 页码：7119 - 7131
• 全文大小：220K
• 年卷期：v.49,no.24(November 30, 2006)
• ISSN：1520-4804

文摘

In the search for a selective adenosine A₁ receptor antagonist with greater aqueous solubility than thecompounds currently in clinical trials as diuretics, a series of 1,4-substituted 8-cyclohexyl and 8-bicyclo[2.2.2]octylxanthines were investigated. The binding affinities of a variety of cyclohexyl and bicyclo[2.2.2]octylxanthines for the rat and human adenosine A₁, A_2A, A_2B, and A₃ receptors are presented.Bicyclo[2.2.2]octylxanthine 16 exhibited good pharmaceutical properties and in vivo activity in a rat diuresismodel (ED₅₀ = 0.3 mg/kg po). Optimization of the bridgehead substituent led to propionic acid 29 (BG9928),which retained high potency (hA₁, K_i = 7 nM) and selectivity for the adenosine A₁ receptor (915-foldversus adenosine A_2A receptor; 12-fold versus adenosine A_2B receptor) with improved oral efficacy in therat diuresis model (ED₅₀ = 0.01 mg/kg) as well as high oral bioavailability in rat, dog, and cynomolgusmonkey.