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Examining the Role of the Linker in Bitopic N6-Substituted Adenosine Derivatives Acting as Biased Adenosine A1 Receptor Agonists
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-06-21 , DOI: 10.1021/acs.jmedchem.2c00320 Jon Kyle Awalt 1 , Anh T N Nguyen 2 , Tim J Fyfe 1 , Bui San Thai 2 , Paul J White 2 , Arthur Christopoulos 2 , Manuela Jörg 1 , Lauren T May 2 , Peter J Scammells 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-06-21 , DOI: 10.1021/acs.jmedchem.2c00320 Jon Kyle Awalt 1 , Anh T N Nguyen 2 , Tim J Fyfe 1 , Bui San Thai 2 , Paul J White 2 , Arthur Christopoulos 2 , Manuela Jörg 1 , Lauren T May 2 , Peter J Scammells 1
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The adenosine A1 receptor is a therapeutic target based on its ability to provide cardioprotection during episodes of myocardial ischemia and reperfusion injury. However, the clinical translation of A1R agonists has been hindered by dose-limiting adverse effects (bradycardia and hypotension). Previously, we demonstrated that the bitopic agonist VCP746 (1), consisting of an adenosine pharmacophore linked to an allosteric moiety, can stimulate cardioprotective A1R signaling effects in the absence of unwanted bradycardia. This study maps the structure–activity relationships of 1 through modifications to the linker moiety. Derivatives differing in the flexibility, length, and nature of the linker were assessed, which revealed that the linker is tolerant of several modifications including added rigidity. Ligands featuring 1,4-disubstituted 1,2,3-triazoles were the most biased of the novel analogues but also displayed sub-nanomolar potency in a cAMP accumulation assay at the A2BR. To our knowledge, 10 is the most potent A2BR agonist published to date.
中文翻译：
检查接头在作为偏向腺苷 A1 受体激动剂的双位 N6 取代腺苷衍生物中的作用
腺苷A 1受体是基于其在心肌缺血和再灌注损伤发作期间提供心脏保护的能力的治疗靶标。然而，A 1 R 激动剂的临床转化受到剂量限制性副作用（心动过缓和低血压）的阻碍。以前，我们证明了由与变构部分连接的腺苷药效团组成的双位激动剂 VCP746 ( 1 ) 可以在没有不需要的心动过缓的情况下刺激心脏保护性 A 1 R 信号传导作用。本研究绘制了1通过对接头部分的修饰。评估了接头的灵活性、长度和性质不同的衍生物，这表明接头可以耐受包括增加刚性在内的多种修饰。以 1,4-二取代 1,2,3-三唑为特征的配体是新型类似物中最有偏见的，但在 A 2B R的 cAMP 积累测定中也显示出亚纳摩尔效力。据我们所知，10是最有效的 A迄今为止发表的2B R 激动剂。
更新日期：2022-06-21
中文翻译：
检查接头在作为偏向腺苷 A1 受体激动剂的双位 N6 取代腺苷衍生物中的作用
腺苷A 1受体是基于其在心肌缺血和再灌注损伤发作期间提供心脏保护的能力的治疗靶标。然而，A 1 R 激动剂的临床转化受到剂量限制性副作用（心动过缓和低血压）的阻碍。以前，我们证明了由与变构部分连接的腺苷药效团组成的双位激动剂 VCP746 ( 1 ) 可以在没有不需要的心动过缓的情况下刺激心脏保护性 A 1 R 信号传导作用。本研究绘制了1通过对接头部分的修饰。评估了接头的灵活性、长度和性质不同的衍生物，这表明接头可以耐受包括增加刚性在内的多种修饰。以 1,4-二取代 1,2,3-三唑为特征的配体是新型类似物中最有偏见的，但在 A 2B R的 cAMP 积累测定中也显示出亚纳摩尔效力。据我们所知，10是最有效的 A迄今为止发表的2B R 激动剂。
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