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Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-07-26 , DOI: 10.1021/acs.jmedchem.9b00106 Marco Betti 1 , Daniela Catarzi 1 , Flavia Varano 1 , Matteo Falsini 1 , Katia Varani 2 , Fabrizio Vincenzi 2 , Silvia Pasquini 2 , Lorenzo di Cesare Mannelli 3 , Carla Ghelardini 3 , Elena Lucarini 3 , Diego Dal Ben 4 , Andrea Spinaci 4 , Gianluca Bartolucci 1 , Marta Menicatti 1 , Vittoria Colotta 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-07-26 , DOI: 10.1021/acs.jmedchem.9b00106 Marco Betti 1 , Daniela Catarzi 1 , Flavia Varano 1 , Matteo Falsini 1 , Katia Varani 2 , Fabrizio Vincenzi 2 , Silvia Pasquini 2 , Lorenzo di Cesare Mannelli 3 , Carla Ghelardini 3 , Elena Lucarini 3 , Diego Dal Ben 4 , Andrea Spinaci 4 , Gianluca Bartolucci 1 , Marta Menicatti 1 , Vittoria Colotta 1
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A new series of amino-3,5-dicyanopyridines (1-31) was synthesized and biologically evaluated in order to further investigate the potential of this scaffold to obtain adenosine receptor (AR) ligands. In general, the modifications performed have led to compounds having high to good human (h) A1AR affinity and an inverse agonist profile. While most of the compounds are hA1AR-selective, some derivatives behave as mixed hA1AR inverse agonists/A2A and A2B AR antagonists. The latter compounds (9-12) showed that they reduce oxaliplatin-induced neuropathic pain by a mechanism involving the alpha7 subtype of nAchRs, similar to the nonselective AR antagonist caffeine, taken as the reference compound. Along with the pharmacological evaluation, chemical stability of methyl 3-(((6-amino-3,5-dicyano-4-(furan-2-yl)pyridin-2-yl)sulfanyl)methyl)benzoate 10 was assessed in plasma matrices (rat and human), and molecular modeling studies were carried out to better rationalize the available structure-activity relationships.
中文翻译：
氨基-3,5-二氰基吡啶核上的修饰以获得具有抗神经病变活性的多方面腺苷受体配体。
为了进一步研究该支架获得腺苷受体（AR）配体的潜力，合成了一系列新的氨基-3,5-二氰基吡啶（1-31），并对其进行了生物学评估。通常，进行的修饰导致化合物具有高至良好的人（h）A1AR亲和力和反向激动剂谱。尽管大多数化合物是hA1AR选择性的，但某些衍生物的作用类似于混合的hA1AR反向激动剂/ A2A和A2B AR拮抗剂。后者的化合物（9-12）显示，它们通过涉及nAchRs的alpha7亚型的机制减轻了奥沙利铂诱导的神经性疼痛，该机制类似于非选择性AR拮抗剂咖啡因，被用作参考化合物。连同药理学评估，甲基3-（（（6-氨基-3，
更新日期：2019-07-15
中文翻译：
氨基-3,5-二氰基吡啶核上的修饰以获得具有抗神经病变活性的多方面腺苷受体配体。
为了进一步研究该支架获得腺苷受体（AR）配体的潜力，合成了一系列新的氨基-3,5-二氰基吡啶（1-31），并对其进行了生物学评估。通常，进行的修饰导致化合物具有高至良好的人（h）A1AR亲和力和反向激动剂谱。尽管大多数化合物是hA1AR选择性的，但某些衍生物的作用类似于混合的hA1AR反向激动剂/ A2A和A2B AR拮抗剂。后者的化合物（9-12）显示，它们通过涉及nAchRs的alpha7亚型的机制减轻了奥沙利铂诱导的神经性疼痛，该机制类似于非选择性AR拮抗剂咖啡因，被用作参考化合物。连同药理学评估，甲基3-（（（6-氨基-3，
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