Synthesis of (E)-8-(3-Chlorostyryl)caffeine Analogues Leading to 9-Deazaxanthine Derivatives as Dual A2A Antagonists/MAO-B Inhibitors

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• 作者：Silvia Rivara ; Giovanni Piersanti ; Francesca Bartoccini ; Giuseppe Diamantini ; Daniele Pala ; Teresa Riccioni ; Maria Antonietta Stasi ; Walter Cabri ; Franco Borsini ; Marco Mor ; Giorgio Tarzia ; Patrizia Minetti
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：1247-1261
• 全文大小：648K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

A systematic modification of the caffeinyl core and substituents of the reference compound (E)-8-(3-chlorostyryl)caffeine led to the 9-deazaxanthine derivative (E)-6-(4-chlorostyryl)-1,3,5,-trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4-(3H,5H)-dione (17f), which acts as a dual human A_2a antagonist/MAO-B inhibitor (K_i(A_2A) = 260 nM; IC₅₀(MAO-B) = 200 nM; IC₅₀(MAO-A) = 10 渭M) and dose dependently counteracts haloperidol-induced catalepsy in mice from 30 mg/kg by the oral route. The compound is the best balanced A_2A antagonist/MAO-B inhibitor reported to date, and it could be considered as a new lead in the field of anti-Parkinson鈥檚 agents. A number of analogues of 17f were synthesized and qualitative SARs are discussed. Two analogues of 17f, namely 18b and 19a, inhibit MAO-B with IC₅₀ of 68 and 48 nM, respectively, being 5鈥?-fold more potent than the prototypical MAO-B inhibitor deprenyl (IC₅₀ = 334 nM).