Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1.
Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1.
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DOI：
10.1038/ncomms2953
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发表时间：
2013
影响因子：
16.6
通讯作者：
Marugan JJ
中科院分区：
文献类型：
--
作者：
Xiao J;Huang Z;Chen CZ;Agoulnik IU;Southall N;Hu X;Jones RE;Ferrer M;Zheng W;Agoulnik AI;Marugan JJ
重组松弛素肽激素的抗纤维化、血管舒张和促血管生成治疗特性已在几种疾病中进行了研究，最近的临床试验数据显示其在治疗急性心力衰竭中的益处。然而，由于这些肽激素的半衰期短且需要静脉内给药，因此难以在慢性环境中研究其重塑能力。在这里，我们提出了第一个小分子系列的人松弛素受体1（RXFP 1）激动剂。这些分子在几种功能测定中显示出与天然激素相似的功效。突变研究表明，小分子通过变构位点激活松弛素受体。这些化合物具有优异的物理和体内药代动力学性质，以支持松弛素生物学的进一步研究和RXFP 1激活的治疗益处的动物功效研究。
The anti-fibrotic, vasodilatory, and pro-angiogenic therapeutic properties of recombinant relaxin peptide hormone have been investigated in several diseases and recent clinical trial data has shown benefit in treating acute heart failure. However, the remodeling capacity of these peptide hormones is difficult to study in chronic settings due to their short half-life and the need for intravenous administration. Here we present the first small-molecule series of human relaxin receptor 1 (RXFP1) agonists. These molecules display similar efficacy as the natural hormone in several functional assays. Mutagenesis studies indicate that the small molecules activate relaxin receptor through an allosteric site. These compounds have excellent physical and in vivo pharmacokinetic properties to support further investigation of relaxin biology and animal efficacy studies of the therapeutic benefits of RXFP1 activation.