Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, United States.
J Med Chem. 2021 Dec 23;64(24):17866-17886. doi: 10.1021/acs.jmedchem.1c01081. Epub 2021 Dec 2.
The central relaxin-3/RXFP3 system plays important roles in stress responses, feeding, and motivation for reward. However, exploration of its therapeutic applications has been hampered by the lack of small molecule ligands and the cross-activation of RXFP1 in the brain and RXFP4 in the periphery. Herein, we report the first structure-activity relationship studies of a series of novel nonpeptide amidinohydrazone-based agonists, which were characterized by RXFP3 functional and radioligand binding assays. Several potent and efficacious RXFP3 agonists (e.g., ) were identified with EC values <10 nM. These compounds also had high potency at RXFP4 but no agonist activity at RXFP1, demonstrating > 100-fold selectivity for RXFP3/4 over RXFP1. ADME and pharmacokinetic assessments revealed that the amidinohydrazone derivatives may have limited brain permeability. Collectively, our findings provide the basis for further optimization of lead compounds to develop a suitable agonist to probe RXFP3 functions in the brain.
中枢松弛素-3/RXFP3 系统在应激反应、摄食和奖励动机中发挥重要作用。然而，由于缺乏小分子配体以及在大脑中交叉激活 RXFP1 和在外周激活 RXFP4，其治疗应用的探索受到了阻碍。在此，我们报告了一系列新型非肽氨甲酰肼基激动剂的首次结构-活性关系研究，这些激动剂通过 RXFP3 功能和放射性配体结合测定进行了表征。鉴定出了几种具有 EC 值 <10 nM 的有效和高效的 RXFP3 激动剂（例如 ）。这些化合物在 RXFP4 上也具有高 potency，但在 RXFP1 上没有激动活性，对 RXFP3/4 相对于 RXFP1 的选择性 >100 倍。ADME 和药代动力学评估表明，氨甲酰肼衍生物可能具有有限的脑渗透性。总的来说，我们的发现为进一步优化先导化合物以开发合适的激动剂来研究 RXFP3 在大脑中的功能提供了基础。
