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首页> 外文期刊>Journal of Medicinal Chemistry >Design, synthesis, and evaluation of proline and pyrrolidine based melanocortin receptor agonists. A conformationally restricted dipeptide mimic approach
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Design, synthesis, and evaluation of proline and pyrrolidine based melanocortin receptor agonists. A conformationally restricted dipeptide mimic approach

机译：设计，合成和评估基于脯氨酸和吡咯烷的黑皮质素受体激动剂。构象受限的二肽模拟方法

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摘要

The design, synthesis, and structure-activity relationships (SAR) of a series of novel proline and pyrrolidine based melanocortin receptor (MCR) agonists are described. To validate a conformationally constrained Arg-Nal dipeptide analogue strategy, we first synthesized and evaluated a test set of cis-(2R, 4R)-proline analogues (21a-g). All of these compounds showed significant binding and agonist potency at the hMC1R, hMC3R, and hMC4R. Potent cis-(2S,4R)-pyrrolidine based MCR agonists (35a-g) were subsequently developed by means of this design approach. A SAR study directed toward probing the effect of the two chiral centers in the pyrrolidine ring on biological activity revealed the importance of the (S) absolute configuration at the 2-position for binding affinity, agonist potency, and receptor selectivity. Among the four sets of the pyrrolidine diastereomers investigated, analogues with the (2S, 4R) configuration were the most potent agonists across the three receptors, followed by those possessing the (2S,4S) configuration.
机译：描述了一系列新型脯氨酸和吡咯烷类黑皮质素受体（MCR）激动剂的设计，合成和构效关系（SAR）。为了验证构象受限的Arg-Nal二肽类似物策略，我们首先合成并评估了顺-（2R，4R）-脯氨酸类似物（21a-g）的测试集。所有这些化合物在hMC1R，hMC3R和hMC4R上均显示出显着的结合和激动剂效能。随后通过这种设计方法开发了强效的顺-（2S，4R）-吡咯烷基MCR激动剂（35a-g）。一项旨在探索吡咯烷环中两个手性中心对生物活性影响的SAR研究表明，在2位上的（S）绝对构型对于结合亲和力，激动剂效能和受体选择性很重要。在所研究的四组吡咯烷非对映异构体中，具有（2S，4R）构型的类似物是跨越三种受体的最有效的激动剂，其次是具有（2S，4S）构型的激动剂。

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