Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower St, London WC1E 6DH, U.K.
William Harvey Research Institute, Barts & The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, U.K.
J Med Chem. 2022 Apr 14;65(7):5495-5513. doi: 10.1021/acs.jmedchem.1c01974. Epub 2022 Mar 25.
C-type natriuretic peptide (CNP) is involved in the regulation of vascular homeostasis, which is at least partly mediated through agonism of natriuretic peptide receptor C (NPR-C), and loss of this signaling has been associated with vascular dysfunction. As such, NPR-C is a novel therapeutic target to treat cardiovascular diseases. A series of novel small molecules have been designed and synthesized, and their structure-activity relationships were evaluated by a surface plasmon resonance binding assay. The biological activity of hit compounds was confirmed through organ bath assays measuring vascular relaxation and inhibition of cAMP production, which was shown to be linked to its NPR-C activity. Lead compound was identified as a potent agonist (EC ∼ 1 μM) with promising pharmacokinetic properties.
C 型利钠肽（CNP）参与血管内环境稳态的调节，至少部分通过利钠肽受体 C（NPR-C）的激动作用介导，这种信号的丧失与血管功能障碍有关。因此，NPR-C 是治疗心血管疾病的一种新的治疗靶点。已经设计和合成了一系列新的小分子，并通过表面等离子体共振结合测定法评估了它们的构效关系。通过测量血管舒张和抑制环磷酸腺苷产生的器官浴测定来确认命中化合物的生物学活性，这被证明与其 NPR-C 活性有关。先导化合物 被鉴定为具有有前途的 药代动力学特性的强效激动剂（EC∼1μM）。
