Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity

被引：17

作者：

Betti, Marco ^{[1
]}

Catarzi, Daniela ^{[1
]}

Varano, Flavia ^{[1
]}

Falsini, Matteo ^{[1
]}

Varani, Katia ^{[2
]}

Vincenzi, Fabrizio ^{[2
]}

Pasquini, Silvia ^{[2
]}

Mannelli, Lorenzo di Cesare ^{[3
]}

Ghelardini, Carla ^{[3
]}

Lucarin, Elena ^{[3
]}

Dal Ben, Diego ^{[4
]}

Spinaci, Andrea ^{[4
]}

Bartolucci, Gianluca ^{[1
]}

Menicatti, Marta ^{[1
]}

Colotta, Vittoria ^{[1
]}

机构：

[1] Univ Firenze, Sez Farmaceut & Nutraceut, Area Farmaco & Salute Bambino, Dipartimento Neurosci,Psicol, Via Ugo Schiff 6, I-50019 Sesto Fiorentino, Italy

[2] Univ Ferrara, Sez Farmacol, Dipartimento Sci Med, Via Fossato Mortara 17-19, I-44121 Ferrara, Italy

[3] Univ Firenze, Sez Farmacol & Tossicol, Area Farmaco & Salute Bambino, Dipartimento Neurosci,Psicol, Viale Pieraccini 6, I-50139 Florence, Italy

[4] Univ Camerino, Scuola Sci Farmaco & Prod Salute, Via S Agostino 1, I-62032 Camerino, Macerata, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 15期

关键词：

NEUROPATHIC PAIN; PHARMACOLOGICAL CHARACTERIZATION; STRUCTURAL INVESTIGATIONS; ANTAGONISTS; SYNTHESIS; SELECTIVE ANTAGONISTS; GENETIC ALGORITHM; INVERSE AGONISTS; HIGHLY POTENT; MOUSE MODEL; ONE-STEP;

D O I：

10.1021/acs.jmedchem.9b00106

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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) A(1)AR affinity and an inverse agonist profile. While most of the compounds are hA(1)AR-selective, some derivatives behave as mixed hA(1)AR inverse agonists/A(2A) and A(2B) 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.

引用

页码：6894 / 6912

页数：19

共 84 条

[31] The 1,2,4-Triazolo[4,3-a]pyrazin-3-one as a Versatile Scaffold for the Design of Potent Adenosine Human Receptor Antagonists. Structural Investigations to Target the A2A Receptor Subtype [J].