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首页> 外文期刊>Journal of Medicinal Chemistry >7-Substituted 5-amino-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidines as A2A adenosine receptor antagonists: a study on the importance of modifications at the side chain on the activity and solubility.
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7-Substituted 5-amino-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidines as A2A adenosine receptor antagonists: a study on the importance of modifications at the side chain on the activity and solubility.

机译：7位取代的5-氨基-2-（2-呋喃基）吡唑并（4,3-e）-1,2,4-三唑并（1,5-c）嘧啶类化合物作为A2A腺苷受体拮抗剂的研究在侧链上修饰活性和溶解性。

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It was demonstrated in the early 1990s that adenosine exerts many physiological functions through the interaction with four different receptors, named A1, A2A, A2B, and A3. In the past few years, our group has been involved in the development of A2A antagonists, which led to the synthesis of SCH 58261 (1), the first potent and selective adenosine A2A antagonist, which has been widely used as a reference compound. In this paper, we present an extended series of pyrazolotriazolopyrimidines synthesized with the aim to investigate the influence of the substitutions on the pyrazole ring. The choice of the substituents was based on their capability to improve water solubility while retaining high affinity and selectivity at the human A2A adenosine receptor subtype. In this series, some structural characteristics that are important for activity, i.e., tricyclic structure, free amino group at 5-position, furan ring, and substituent at 7-position on the pyrazole moiety, have been maintained. We focused our attention on the nature of the phenyl ring substituent to improve water solubility. Following this strategy, we developed new compounds with good affinity and selectivity for A2A adenosine receptors, such as 8d (K(i) 0.12 nM; hA1/hA2A ratio = 1025; R(m) = 2.8), 8h (K(i) 0.22; hA1/hA2A ratio = 9818; R(m) = 3.4), 8i (K(i) 0.18 nM; hA1/hA2A ratio = 994; R(m) = 2.8), 8k (K(i) 0.13 nM; hA1/hA2A ratio = 4430; R(m) = 3.6), and 14b (K(i) 0.19 nM; hA1/hA2A ratio = 2273; R(m) = 2.7). All the new synthesized compounds have no significant interaction with either A2B or A3 receptor subtypes. This new series of compounds deeply enlightens some structural requirements to display high affinity and selectivity for the A2A adenosine receptor subtype, although our goal of identifying new compounds with increased water solubility was not completely achieved. On this basis, other strategies will be devised to improve this class of compounds with a profile that appears to be promising for treatment of neurodegenerative disorders, such as Parkinson's disease.
机译：在1990年代初期，腺苷通过与四种不同的受体A1，A2A，A2B和A3相互作用而发挥许多生理功能。在过去的几年中，我们的研究小组一直致力于A2A拮抗剂的开发，从而导致了SCH 58261（1）的合成，这是第一种有效的选择性腺苷A2A拮抗剂，已被广泛用作参考化合物。在本文中，我们提出了一系列扩展的吡唑并三唑并嘧啶，目的是研究取代基对吡唑环的影响。取代基的选择基于它们改善水溶性的能力，同时保持对人A2A腺苷受体亚型的高亲和力和选择性。在该系列中，保持了对于活性重要的一些结构特征，即三环结构，吡唑部分上5-位的游离氨基，呋喃环和7位上的取代基。我们将注意力集中在苯环取代基的性质上，以改善水溶性。按照这一策略，我们开发了对A2A腺苷受体具有良好亲和力和选择性的新化合物，例如8d（K（i）0.12 nM; hA1 / hA2A比= 1025; R（m）= 2.8），8h（K（i） 0.22; hA1 / hA2A比= 9818; R（m）= 3.4），8i（K（i）0.18 nM; hA1 / hA2A比= 994; R（m）= 2.8），8k（K（i）0.13 nM; hA1 / hA2A比= 4430; R（m）= 3.6）和14b（K（i）0.19 nM; hA1 / hA2A比= 2273; R（m）= 2.7）。所有新合成的化合物均与A2B或A3受体亚型无显着相互作用。这个新系列的化合物对A2A腺苷受体亚型显示出高亲和力和选择性具有深远的结构要求，尽管我们鉴定水溶性增加的新化合物的目标并未完全实现。在此基础上，将设计出其他策略来改善此类化合物，使其具有治疗神经退行性疾病（如帕金森氏病）的前景。

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