Indole-Containing Amidinohydrazones as Nonpeptide, Dual RXFP3/4 Agonists: Synthesis, Structure-Activity Relationship, and Molecular Modeling Studies.
Indole-Containing Amidinohydrazones as Nonpeptide, Dual RXFP3/4 Agonists: Synthesis, Structure-Activity Relationship, and Molecular Modeling Studies.
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DOI：
10.1021/acs.jmedchem.1c01081
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发表时间：
2021-12-23
影响因子：
7.3
通讯作者：
Jin C
中科院分区：
文献类型：
--
作者：
Guan D;Rahman MT;Gay EA;Vasukuttan V;Mathews KM;Decker AM;Williams AH;Zhan CG;Jin C
中枢松弛素-3/RXFP3系统在应激反应、摄食和奖励动机中起重要作用。然而，由于缺乏小分子配体以及大脑中RXFP 1和外周中RXFP 4的交叉激活，其治疗应用的探索受到阻碍。在此，我们报告了一系列新的非肽脒基腙类激动剂，其特征在于RXFP 3功能和放射性配体结合试验的第一个构效关系的研究。几种有效的RXFP 3激动剂（例如，10 d）的EC 50值<10 nM。这些化合物对RXFP 4也具有高效力，但对RXFP 1没有激动剂活性，表明对RXFP 3/4的选择性超过RXFP 1> 100倍。体外ADME和药代动力学评估显示，脒基腙衍生物可能具有有限的脑渗透性。总的来说，我们的研究结果为进一步优化先导化合物提供了基础，以开发合适的激动剂来探测RXFP 3在大脑中的功能。
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., 10d) were identified with EC50 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. In vitro 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.
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影响因子：
14.8
作者：
Kozakov D;Hall DR;Xia B;Porter KA;Padhorny D;Yueh C;Beglov D;Vajda S
通讯作者：
Vajda S
DOI：
10.1124/jpet.104.073486
发表时间：
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作者：
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影响因子：
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作者：
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